ImmuDocs funded projects

Main supervisor: Laura Airas, Turku PET Centre, Neurocenter, Turku University Hospital, Clinical Neurosciences, University of Turku, inFLAMES Research Flagship, laura.airas@utu.fi

Other supervisor(s):  Maija Saraste, Clinical Neurosciences, University of Turku, NeuroCenter, Turku University Hospital, Turku PET Centre, inFLAMES Research Flagship, maija.saraste@utu.fi

Doctoral researcher: Abhijith Yenikekaluva

Pilot project description 

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), in which activated peripheral and CNS resident immune cells promote inflammation leading to destruction of myelin sheets and eventually to irreversible neuro-axonal damage. After initial relapsing-remitting disease course, disability starts to progress steadily in a large proportion of people with MS. This progressive clinical decline is driven by chronic activation of microglia, the CNS resident innate immune cells. Previous studies have shown that both focal microglial activation at the edge of chronic active lesions and widespread microglial activation outside the lesions in so-called normal appearing white matter is harmful and associates with later disability.

Microglial activation can be quantified in vivo using positron emission tomography (PET) and radioligands binding to 18 kDa translocator protein (TSPO), such as [11C]PK11195. The primary aim of the proposed project is to explore for direct evidence that TSPO-PET-detectable microglial activation is detrimental for brain integrity. The hypothesis is that higher microglial activation will be associated with greater lesion growth and brain atrophy. Selected doctoral researcher will join the research group of Professor Laura Airas at Department of Clinical Neurosciences, University of Turku. The researcher will acquire good knowledge of immunological mechanisms driving progression of MS, and get familiar with PET and MRI methodology and processing, and statistical analysis procedures.

The results of the study will provide first proof of concept that microglial activation at the edge of lesions will lead to enlargement of lesions and brain atrophy, and thus promote progression of MS. It will provide a more complete picture of the association of innate immune cell activation and disease progression, and might thus in the future aid development of new, microglia-targeting treatment options for progressive MS.

Keywords:

Multiple sclerosis, imaging, TSPO-PET, innate immune cell, microglia

Main supervisor: Laura Airas, Turku PET Centre, Neurocenter, Turku University Hospital, Clinical Neurosciences,
University of Turku, inFLAMES Research Flagship, laura.airas@utu.fi

Other supervisor(s): Maija Saraste, Clinical Neurosciences, University of Turku, Neurocenter,
Turku University Hospital, Turku PET Centre, inFLAMES Research Flagship, maija.saraste@utu.fi

Doctoral researcher: Venla Ahola

Pilot project description

MS relapses can be kept under control with efficient immunotherapies, but despite this, many patients experience progressive clinical decline driven by microglial activation and interaction between microglia and astrocytes. Microglial activation can be detected in vivo by using PET and [11C]PK11195–ligand, which binds to 18 kDa translocator protein (TSPO) in microglia. However, PET is rather expensive and difficult method to use; hence, biomarkers that would reflect neuroinflammation and reactive gliosis, and could be measured from blood are needed.
The primary aim of this project is to evaluate the association between TSPO-PET measurable microglial activation and blood levels of biomarkers reflecting microglial activation and/or reactive astrocytosis (Chitinase 3-like 1 (CHI3L1), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neopterin) in MS. In addition, association of CHI3L1, sTREM2 and neopterin with clinical and MRI data will be assessed. The study cohort consists of 80 MS-patients and 25 healthy controls. The doctoral researcher will analyse the existing biomarker, imaging and clinical data, and perform ELISA-analyses to test the following hypotheses.
1. Microglial activity measured with TSPO-PET increases with advancing MS disease, along with an increase in concentration of CHI3L1, sTREM2 and neopterin.
2. CHI3L1, sTREM2 and neopterin increase with disease progression and increasing smoldering disease when measured longitudinally.
3. CHI3L1, sTREM2 and neopterin will associate with signs of neuroaxonal damage measured using DTI-MRI and serum NfL.
The results will give important information about the usability of CHI3L1, sTREM2 and neopterin as surrogate markers of the pathogenic mechanisms driving MS progression. Such markers would be useful in monitoring disease progression both in clinic and in clinical trials. The results will be reported in three papers published in high-impact peer-reviewed international scientific journals.

Key words:
Multiple sclerosis, TSPO-PET, microglia, CHI3L1, Neopterin, sTREM2

Main supervisor: PhD Jonna Alanko, Medicity, University of Turku, Principal Investigator (Academy Research Fellow), jonna.alanko@utu.fi

Other supervisor(s):  Prof Marko Salmi, InFLAMES and Medicity, University of Turku
Website: https://sites.utu.fi/salmilab/

Doctoral researcher: Pauline Weinzettl

Pilot project description

Efficient and directional immune cell migration is crucial for functioning immune system. Efficient longdistance navigation is especially critical for antigen presenting dendritic cells (DCs), which transport pathogen derived antigens from peripheral tissues into lymph nodes for T cell activation. The direction of migration is determined by attracting chemokines, but how chemokine gradients are maintained and regulated in tissues to ensure efficient DC migration in changing conditions has remained unclear. Defects in DC migration can lead to various autoimmune disorders, and the same chemokines can be utilized by metastasizing cancer cells. Therefore, understanding chemokine directed leukocyte migration is highly important for the development of future therapies for various diseases.

Our previous work has revealed an unexpected role for DCs in the generation of CCR7-dependent chemokine gradients (Alanko et al. 2023 Science Immunology). In the present ImmuDocs project, the role of this novel phenomenon will be further investigated in different tissue environments along with the detailed mechanism of gradient generation and receptor mediated chemokine uptake. The main techniques used in the project include in vitro cell culturing and DC differentiation, unique cell migration setups, quantitative live cell microscopy, cell-derived matrixes, Western Blotting, FACS as well as CRISPRCas9 mediated gene manipulation. The work will be conducted with international collaborators in a vibrant newly established research group at Medicity in University of Turku, surrounded by Turku Bioscience with several state-of-the-art core facilities, including the Euro BioImaging Finnish Advanced Light Microscopy Node. The applicant is expected to have good knowhow on immunology/cell biology and at least some of the above listed techniques. Together, the project aims to reveal the unknown aspects of DC chemotaxis and set the stage for novel therapeutic innovations.

Key words: dendritic cells, chemotaxis, cell migration, extracellular matrix, CCR7, microscopy techniques

Main supervisor: Jukka Alinikula, Institute of Biomedicine, University of Turku, jukka.alinikula@utu.fi,
https://www.utu.fi/en/people/jukka-alinikula

Other supervisor(s):
Pieta Mattila, InFLAMES Flagship, Turku Bioscience Centre, Institute of Biomedicine, University of Turku, pieta.mattila@utu.fi, https://mattilalab.utu.fi/

Doctoral researcher: Alina Tarsalainen

Pilot project description

Antibody affinity maturation and effector class switching enable the acquired immune system to function efficiently and precisely. This process requires somatic hypermutation (SHM), where the mutator enzyme AID generates point mutations during immunoglobulin (ig) gene transcription in activated B cells. It is crucial to target AID action to the Ig locus, as off-targeted SHM can lead to B-cell malignancies, while deficiency of SHM can lead to hyper-IgM syndrome and susceptibility to severe infections and poor vaccine responsiveness. We previously showed that Ig enhancers and enhancer-like sequences, as well as transcription factor binding sites within them are vital to the targeting process, but the exact mechanism remains elusive.
This project seeks to reveal the underlying rules and the molecular mechanisms of SHM targeting in the genome. The aims are to reveal (1) Ig enhancer-induced changes in mutating target gene that explain the increased mutation rate, (2) the key sequence features of Ig enhancers that determine how mutation enhancers differ from transcription enhancers, and (3) their role in individuals’ different response to vaccination.
The project will help understand how mutational enhancers work and why, despite intrinsic efforts to confine SHM to the Ig locus, it is occasionally mis-targeted causing lymphoma. The project will provide a rationale for predicting likely mutating genomic loci and development of commercial diagnostic assays and identify potential target molecules for therapeutic targeting of SHM machinery. Gaining insight to inter individual differences in vaccination response will be an important step in optimizing vaccine efficacy and developing personalized vaccination strategies, and e.g., broadly neutralizing antibodies against HIV. The results also have implications in antibody engineering where the manipulation of targeting elements can be utilized in the production of therapeutic or diagnostic antibodies with desired qualities.

Key words:
B cell, humoral immunity, somatic hypermutation, antibodies, lymphoma, vaccination

Main supervisor: Laura Elo, PhD, Professor, Research Director, Turku Bioscience Centre and Institute of Biomedicine,
University of Turku; laura.elo@utu.fi; https://elolab.utu.fi

Other supervisor(s):
Tomi Suomi, PhD, A/Prof., Turku Bioscience Centre, University of Turku; tomi.suomi@utu.fi;
https://www.utu.fi/en/people/tomi-suomi
Markku Varjosalo, PhD, Research Director, Institute of Biotechnology, University of Helsinki;
markku.varjosalo@helsinki.fi; https://researchportal.helsinki.fi/en/persons/markku-varjosalo

Doctoral researcher: Sadia Akram

Pilot project description

Goal: This project aims to harness deep phosphoproteome profiling to uncover molecular mechanisms of immune dysfunction in inborn errors of immunity (IEI), focusing on common variable immunodeficiency (CVID) and severe combined immunodeficiency (SCID). The goal is to understand how dysregulated phosphorylation affects immune signaling in these disorders. By combining advanced computational and experimental techniques and clinical immunology, we aim to identify potential biomarkers and therapeutic targets, bridging critical gaps from bench to bedside.
Context: IEIs like CVID, the most common form, and life-threatening SCID involve defects in immune cell development or function, increasing susceptibility to infections and autoimmunity. Phosphorylation plays a crucial role in regulating immune signaling and its dysregulation can impair immune responses in IEIs. Preliminary data from our labs show altered phosphorylation in key molecules like STAT proteins and B cell receptor components in CVID, suggesting a direct link between aberrant phosphorylation and immune dysfunction.
Approach: This project, based at Turku Bioscience, involves close collaboration between computational, experimental and clinical teams. We will analyze mass spectrometry phosphoproteome data from CVID and SCID patients. Using advanced machine learning, we will develop a computational framework to interpret
phosphorylation patterns, identify novel phosphosites, and predict kinase-substrate interactions specific to IEIs. Key findings will be experimentally validated using kinase assays and phospho-specific antibodies.
Outcomes: We aim to reveal new insights in pathogenic mechanisms of CVID and SCID by identifying key phosphorylation events contributing to immune dysregulation. The computational framework will be widely applicable for phosphoprofiling in other immune disorders. The candidate will gain computational and immunology skills essential for biomedical research and pharmaceutical industry.

Key words: phosphoproteomics, immune regulation, signaling pathways, computational systems immunology, machine learning, inborn errors of immunity

Main supervisor: Laura Elo, PhD, Professor, Research Director, Turku Bioscience Centre and Institute of Biomedicine,
University of Turku; laura.elo@utu.fi; https://elolab.utu.fi

Other supervisor(s): Elisa Närvä, PhD, Adjunct Professor, FICAN West Cancer Centre and Institute of Biomedicine, University
of Turku; elisa.narva@utu.fi; https://narvalab.utu.fi
Tomi Suomi, PhD, Turku Bioscience Centre, University of Turku; tomi.suomi@utu.fi;
https://www.utu.fi/en/people/tomi-suomi

Doctoral researcher: Daniel Giesel

Pilot project description

Objective: This PhD project aims to develop a computational-experimental approach to identify neo-epitopes for potential use in cancer immunotherapy. The novel approach is to model cancer stem cell (CSC) antigens with advanced computational techniques to analyze whole-exome sequencing, RNA-sequencing, and mass spectrometry proteomics profiling data generated with genetically abnormal human pluripotent stem cells (hPSCs).
Background: Human tumors can carry hundreds of mutations that alter the amino acid sequence of a protein, creating immunogenic neo-epitopes, recognized by T cells to mediate anti-tumor immune responses. Discovery of such immunogenic neo-epitopes holds high potential for developing new approaches for personalized cancer immunotherapies. Recent studies have revealed striking similarities between mutations of hPSCs and CSCs, suggesting that hPSCs could be used to model CSCs which are nearly impossible to study with large-scale methods.
Methodology: This project will establish a robust computational framework for the complex task of neoepitope prediction, including identification of individual mutations, discovery of candidate neo-epitopes, and ranking of the candidates based on their predicted immunogenicity and presence in cancer stem cells of patients. Selected top candidate neo-epitopes will then be analyzed by in vitro assays to validate their immunogenic potential and to refine the prediction algorithms.
Expected outcome: The project is expected to yield a list of validated neo-epitopes with high potential for further cancer immunotherapy applications. The developed computational-experimental approach for neoepitope discovery and validation will be widely applicable in future studies. Importantly, the project also contributes to the training of next-generation experts with both computational and immunology skills needed in biomedical research and the pharmaceutical industry.

Key words: neo-epitopes, immuno-oncology, cancer stem cell immunity, computational systems immunology, machine learning, computational tools

Main supervisor: Adj. Professor Carlos Rogerio Figueiredo, Institute of Biomedicine, University of Turku
crdefi@utu.fi 

Research group website:
https://www.miorg.fi  

Other supervisor(s): Professor Menashe Bar-Eli, MD Anderson Cancer Centre, University of Texas, USA
Website: https://faculty.mdanderson.org/profiles/menashe_bar-eli.html 

Doctoral researcher: Xiaoyue Zhang

Pilot project description 

In cancer immunity, dendritic cells (DCs) are essential for the priming and generation of antitumor T cells that target tumors. Our latest review dissects the nature of desert tumors, known for their severe absence of antitumor T cells. Moreover, we demonstrated how desert tumors dispose of several molecular features to suppress local immunogenicity despite their mutational load. Disrupting immunogenic cell DCs impairs anti-tumor immunity and increases resistance to current immune checkpoint therapies (ICT), such as anti-PD1 blockade.  

One prominent way of disrupting DC’s ability to prime T lymphocytes, specifically, cytotoxic T cells is by damping their ability to process and present antigens through MHC-I molecule. Studies are focusing on uncovering novel molecules and pathways that could boost DCs immunogenicity within the tumor microenvironment (TME). On this front, the immunoproteasome, a specialized protease complex, is critically important for shaping the diversity of cancer antigens (immunopeptidome), essential for robust antitumor immune responses. This diversity can facilitate the priming and generation of new antitumor T cells. When tumor signals disrupt immunoproteasome functions, T cell generation drops, weakening cancer immunity and consequent responses to cancer immunotherapies, such as anti-PD1 blockade.  

The Medical Immuno-Oncology Research Group (MIORG) at the University of Turku has uncovered a novel autocrine immune factor produced by DCs. This factor is key to activating the immunoproteasome, which in turn boosts antigen processing and MHC-I expression on DCs for better T cell priming. In this project, we are investigating how the deficiency in this factor negatively impacts the immune landscape of skin melanoma. We also aim to validate approaches that increase its levels in DCs, boosting T cell generation in combination with anti-PD1 therapy, laying the rationale for future development of new combinatorial immunotherapies.

Keywords: Immune Checkpoint Therapy; Cancer; Immunoproteasome; Cold Tumors; anti-PD1; cross-presentation; Innate Immunity 

Adj. Professor Carlos Rogerio Figueiredo, Institute of Biomedicine, University of Turku, InFLAMES Research Flagship, rogerio.defigueiredo@utu.fi

Other supervisor(s):  Professor Klaus Elenius, Turku Bioscience Centre, University of Turku

Doctoral researcher: Yuwen Chen

Pilot project description 

In the adjuvant treatment of metastatic cutaneous melanoma, where therapy is aimed at preventing recurrence after tumor removal, clinical trials comparing targeted therapy (TT) and immune checkpoint inhibitors (ICI) highlight a balance between short-term control and long-term survival. TT rapidly shrinks tumors by blocking melanoma growth pathways, lowering the risk of recurrence for some patients. Meanwhile, ICIs reinvigorate the immune system to attack cancer cells, providing slower but more durable responses.

When it comes to combining these therapies to achieve better benefits, the order in which they are administered plays a significant role in their effectiveness. One recent clinical trial shows that when TT is used first, it may provide immediate control by shrinking micrometastases in some patients, but it also diminishes the effectiveness of ICI when introduced afterward. Conversely, starting with ICI helps maintain a stronger and more durable immune response, but without the initial rapid tumor control that is typically seen when TT is administered first. In our latest review, we highlight that one of the primary causes of resistance to ICI in melanoma stems from the nature of desert tumors, which are characterized by a lack of antitumor T cells.

Therefore, we hypothesize that TT may contribute to ICI resistance by targeting immune cells responsible to trigger melanoma immunogenicity, suppressing immune response before ICI is introduced.

Our project aims to explore the underlying causes of TT induced ICI resistance in the adjuvant setting, particularly on how it impacts the maintanence of antitumor T cell responses. This knowledge will guide future strategies for rational combinations that retain the initial benefits of TT while supporting the longterm efficacy of ICI. By focusing on the mechanisms through which TT disrupts immune responses, we can develop optimized approaches that prevent recurrence and improve survival outcomes.

Keywords:

Immune checkpoint therapy, cancer, targeted therapy, cold tumors, anti-PD1, adjuvant therapy, resistance

Main supervisor: Pauliina Hartiala, MD, PhD, Docent of Surgery, Specialist in Plastic Surgery, Medicity Research Laboratories, University of Turku, InFLAMES Research Flagship, Department of Plastic and General surgery, Turku University Hospital
pauliina.hartiala@utu.fi, https://www.utu.fi/fi/ihmiset/pauliina-hartiala

Other supervisor(s): Gabriela Martinez-Chacon, PhD, Medicity Research Laboratories, University of Turku, InFLAMES Research Flagship, Department of Plastic and General surgery, Turku University Hospital
mgmcha@utu.fi, https://www.utu.fi/en/people/gabriela-martinez-chacon
Marko Salmi, MD, PhD, Professor, Medicity Research Laboratories, InFLAMES Research Flagship
masalmi@utu.fi, https://www.utu.fi/fi/ihmiset/marko-salmi

Doctoral researcher: Martin Rosenborg

Pilot project description

Breast cancer related lymphedema affects 20-40% of breast cancer patients after axillary lymph node removal and is characterized by interstitial fluid accumulation, adipose tissue hypertrophy, fibrosis and chronic inflammation of the affected arm. There is no definitive cure available.
Our unpublished study using scRNAseq revealed a higher number of type 2 innate lymphoid cells (ILC2s) in lymphedema adipose tissue compared to control adipose tissue. These cells react to stimuli from the environment (lipid mediators, hormones and cytokines), induce a Th2 immune response and interact with various other cell types. We also discovered that ILC2 cells are the only immune cell type in adipose tissue expressing the receptor for a specific lipid mediator, which is already a target of a drug with a different indication making it an intriguing target for future therapies.
This project aims to: 1. Clarify the immune response driving lymphedema using patient samples, 2. Determine the role of ILC2s in maintaining Th2 inflammation and fibrosis in lymphedema and 3. Assess therapeutic strategies targeting ILC2-driven inflammation and fibrosis.
The first subproject (1) focuses on characterization of immune cells and especially the ILC2 in lymphedema tissues through spectral flow cytometry (FLOW) and immunofluorescence (IF) staining. The second subproject (2) focuses on studying the interactions of ILC2 cells and fibroblasts using co-culture experiments. The third subproject (3) focuses on testing treatments targeting lipid mediator signalling in ILC2. Our preliminary data indicate that ILC2s could be central to the disease’s inflammatory and fibrotic processes. The ultimate goal is to utilize drug repurposing options to create novel treatments, potentially transforming lymphedema management. The work is carried out in Medicity research laboratories.

Key words: inflammation, innate lymphoid cell, fibrosis, lymphedema, novel treatment

Main supervisor: Qiushui He, Institute of Biomedicine, University of Turku

Other supervisor(s): Lauri Ivaska, Department of Pediatrics, Turku University Hospital

Doctoral researcher: Denise Anabe

Pilot project description

If the applicant applies for the position through this pathway, this description will serve as a public description of the project if the project is funded by the ImmuDocs Pilot.
Pertussis is a highly contagious respiratory disease caused by Bordetella pertussis bacteria. Despite extensive vaccinations, the disease has resurged. The WHO estimates that there are 16 million cases annually and approximately 195,000 deaths in children globally. This is partly attributed to the waning vaccine-induced immunity and individual variation in vaccine responses associated with genetic polymorphisms. This project aims to explore how genetic polymorphisms contribute to low responses after an acellular pertussis (aP) booster vaccination. We hypothesize that this variability arises from genetic polymorphisms that affect expressions of key proteins, e.g., IL-17, IL-10, and TLR4, involved in pertussis immunity. This research is being carried out at the Institute of Biomedicine, University of Turku. Two clinical studies were conducted: the Booster Pertussis Vaccine Study (BERT) in four age groups (N=124) and the Maternal Immunization Study in Finland (MIFI) (N=138, 69 mother-infant pairs) that aimed to characterize antibody and cellular responses after an aP booster. Serial blood samples were collected for the BERT cohort (before, 1 month, and 1 year after booster), MIFI mothers (before, at delivery, and when the baby was 6 months), and MIFI infants (cord blood, 3 months (pre-vaccination), and 6 months (post-2 primary doses)). The 3- and 4-year follow-up is being conducted from the MIFI cohort. The quantity and function of antibodies, memory B cells, and T cell subsets (BERT) to vaccine antigens have been measured. By using integrated approaches, including genotyping, HLA typing, multiplex immunoassay, and flow cytometry, we will be able to identify certain genotypes/haplotypes to pre- and post-vaccination immune profiles that are associated with low responses to pertussis vaccination in Finnish populations. The results of this study have both scientific value for the development of new vaccines and practical implications for vaccination programs worldwide.

Key words: Pertussis, Acellular vaccine, Genetic polymorphisms, Cytokines, Toll-like receptors, HLA

Main supervisor: Qiushui He, Institute of Biomedicine, University of Turku

Other supervisor(s): Lauri Ivaska, Department of Pediatrics, Turku University Hospital

Doctoral researcher: Ali Shamani

Pilot project description:

Despite vaccinations, pertussis continues to re-emerge in the world. Since mid-2023, the number of reported pertussis cases has significantly increased in Europe. In Finland, 130 laboratory-diagnosed cases are reported in 2023. Until 31.7.2024, 977 cases are reported, being 7.5 fold higher than 2023. Currently, pertussis booster vaccinations are used more broadly in Finland than anywhere else in the world. In addition to 3 primary doses in infancy, boosters are given at 4, 14, and 25 years. THL recommends give a dTap booster every 5 years to health care workers taking care of infants. This strategy is logical because of the rapid waning of immunity after dTap vaccination. However, data regarding the impact of repeated booster vaccination on immune responses and duration of immunity is unknown.

This study aims to investigate pertussis immunity and vaccine responses in health care workers of the wellbeing services county of Southwest Finland (Varha) who have more than 4 years from their previous dTap vaccination and who are due to be vaccinated. We hypothesize that 1) many of the health care workers have low levels of pertussis antibodies prior to booster vaccination, 2) pre-existing immunity before the vaccination determines quantity and quality of the vaccine response measured 4 weeks after the vaccination. The study is registered in EU Clinical Trial database (EU CT 2024-511478-56-00) and approved by Finnish Medicines Agency (Dnro FIMEA/2024/002410). Blood and mucosal samples are collected before and one month after the vaccination, quantity and functionality of (mucosal) antibodies to vaccine antigens, and specific B memory cells and T-cells will be determined, and the integrated analyses are performed. The study will provide new information on the potential effect of the frequent use of boosters on both humoral and cellular immunity. It will also have direct practical implications for vaccination programs in Finland and have high international scientific value.

Key word(s): Pertussis, Acellular vaccine, (Repeated) Booster vaccinations, Antibodies, T cells, Adults

Main supervisor: Jyrki Heino,  M.D., Ph.D., professor, department head, Department of Life Technologies, University of Turku

Other supervisor(s):
Veli–Matti Kähäri, M.D., Ph.D., professor and chief physician, Department of Dermatology, University of Turku and Turku University Hospital
Elina Siljamäki, Ph.D., Docent, Department of Life Technologies, University of Turku

Doctoral researcher: Emmi Virtanen

Pilot project description

Malignant tumours consist of transformed cancer cells, and of numerous other cell types including cancer associated fibroblasts (CAFs), tumour associated macrophages (TAMs), neutrophils, lymphocytes and endothelial cells. All cell types regulate each others’ phenotype and behaviour and cancer progression. Extracellular matrix (ECM) – mainly produced by CAFs – is an important component of tumour microenvironment. ECM has major impact on cancer cells, on the efficacy of immunotherapies and finally on the disease outcome.

We have developed new 3D spheroid based methods to study the interactions of different cell types: human cutaneous squamous cellular carcinoma (cSCC) cells, CAFs and TAMs/neutrophils. Using e.g. mass spectrometry, RNA-sequencing, microscopy and cellular assays for proliferation, phenotype/plasticity and invasion the project aims to unveil the TAM and neutrophil based regulatory mechanisms of invasion and ECM remodelling. Furthermore, our preliminary results have revealed the remarkable plasticity of TAMs. The project aims to find molecular mechanisms used by CAFs and cSCC cells to regulate TAM phenotype.

In our recent paper we showed that spheroid model can be used to successfully screen potential drug molecules (Siljamäki et al., Oncogene, 2023). In this project the spheroids containing three different cell types will be used to test the effects of the inhibitors of critical signalling pathways. The model also allows to test putative drug molecules targeted to macrophages and neutrophils.

Finally, we have recently established a method to combine laser capture microscopy to mass spectrometry and shown that it is possible to get detailed information about e.g. ECM composition in different tumour areas of paraffin embedded SCC tumours and their metastases. This in vivo information is critical for interpretation of the results from in vitro experiments focused on the effects of macrophages and neutrophils on the composition and organization of ECM. (1998 / 2000)

Key words: Macrophage, Neutrophil, Fibroblast, Tumor stroma, Extracellular matrix, Drug development

Main supervisor: Adj Prof. Maija Hollmén, Medicity Research Facility and InFLAMES Flagship
https://hollmenlab.com/

Other supervisor(s): PhD Miro Viitala, Medicity Research Laboratory

Doctoral researcher: Mahalakshmi Karthikeyan

Pilot project description

Enhancing cross-presentation within the tumor microenvironment (TME) is crucial for cancer immunotherapy, reinforcing immune surveillance to detect and reject tumor cells, thus impeding cancer progression. Tumor-associated macrophages (TAMs) are major contributors to resistance formation and effective suppressors of antitumor immune responses. Although, macrophage targeting has proven to be a difficult task, they are evidently a key component of the TME and should not be overlooked to make significant advances in the treatment of refractory and metastatic cancers. This project aims to harness the abundance of TAMs and transform them into effective antigen-presenting cells, hypothesizing that macrophages have untapped potential to expose cancer cells to immune recognition.
The specific aims of the project are: 1) Identify novel targets in macrophages to enhance their crosspresentation of cancer-derived antigens. 2) Develop a human system to study antigen-specific T cell cytotoxicity in the presence of cross-presentation–enhanced macrophages. 3) Analyze the macrophage HLAI peptidome post-target knockout for neoantigen cross-presentation.
Understanding and mitigating tumor-supportive macrophage functions are critical for enhancing current cancer immunotherapies. This approach can reveal new molecules regulating interactions among cancer cells, macrophages, and CD8+ T cells, serving as potential drug targets. This research has the potential for significant scientific discoveries in macrophage immunobiology and real-world benefits for cancer patients with refractory cancers.

Key words: Cancer, macrophage, cross-presentation, CRISPR, neoantigen,
immunopeptidome

Main supervisor: Adj Prof. Maija Hollmén, Medicity Research Facility and InFLAMES Flagship
https://hollmenlab.com/

Other supervisor(s): PhD Rita Turpin, Medicity Research Facility, rita.turpin@utu.fi

Doctoral researcher: Jesper Mickos

Pilot project description

The precise therapeutic control of myeloid malignancies and cancer-driven immune dysfunction remains a critically unmet challenge that has not been successfully addressed with the current arsenal of drugs. Targeting Clever-1, a scavenger receptor expressed by both immunosuppressive macrophage populations and myeloid leukemia cells presents a way to kill two birds with one stone. As such, an antibody targeting Clever-1 (bexmarilimab) is currently under investigation in the BEXMAB phase I/II trial in combination with standard of care, azacytidine, in acute myeloid leukemia and myelodysplastic syndrome.

In this project, we will integrate concurrent efficacy data, obtained from the BEXMAB trial, and detailed molecular level information about bexmarilimab’s mechanism-of-action by single-cell RNA sequencing of patient bone marrow samples before and after treatment. We will also implement mouse models of chemotherapy-induced leukopenia to study Clever-1–regulated hematopoietic recovery, a phenomenon observed in BEXMAB patients after bexmarilimab administration. Altogether, this project aims to understand the homeostatic functions of Clever-1 in the bone marrow and to improve the clinical outcome of patients with myeloid leukemias.

The study is performed in Medicity Research Laboratory at the University of Turku. The applicant should have good knowledge in animal experimentation, multicolor flow cytometry and be proficient in using R.

Key word(s): hematopoiesis, leukemia, macrophages, mouse models, sc-RNAseq, clinical trial

Main supervisor: Jukka Hytönen, Institute of Biomedicine, University of Turku, jukka.hytonen@utu.fi
Other supervisor(s): Jukka Alinikula, Institute of Biomedicine, University of Turku, juilal@utu.fi
Annukka Pietikäinen, Tyks Laboratories, Clinical microbiology, annukka.pietikainen@varha.fi

Doctoral researcher: Varpu Rinne

Pilot project description

Lyme borreliosis (LB), caused by the spirochete Borrelia burgdorferi sensu lato (borrelia), is the most important tick-transmitted disease globally, whose public health burden continues to grow substantially. Borrelia induces strong T-independent B cell responses and disturbed germinal center formation. The bacteria induce continuous antibody production, which is, however, inefficient in creating long-term neutralizing immunity. The uncontrolled infection can spread to the central nervous system (CNS), causing Lyme neuroborreliosis (LNB), where borrelia causes ectopic germinal center formation and long-lasting antibody production within the CNS. How borrelia manipulates the immune response and causes pervasive infection is not known.
Current laboratory diagnostics of LB have significant gaps underlining the need to develop novel methodology. This need can be met through an increased understanding of the immunopathogenesis of LB and the host response in LB. Specifically, we need novel immune-based approaches for the laboratory detection of early LB, for the differentiation of an ongoing LB from a previously treated infection, and for diagnosing LNB using serum samples without requiring invasive cerebrospinal fluid (CSF) sampling.
Our research seeks to reveal the complex mechanisms governing host immune responses during borrelia infection by profiling the immune cells of borrelia-infected mice and of LNB patients, and by comparing the borrelia-induced immune response to control stimulus-induced responses. Especially groundbreaking will be the analysis of CSF immune cells of LNB patients. Single-cell RNA sequencing (scRNA-seq) emerges as a powerful tool in infection immunology research, offering unparalleled resolution to dissect immune response mechanisms in LB/LNB. Through scRNA-seq, we will reveal the immunological details underlying the peculiar immune response in LB/LNB, and at the same, we will identify new methods for diagnostics of the infection.

Key words: Immune response; neuroinflammation; germinal center; Lyme borreliosis; Borrelia burgdorferi; single-cell RNA sequencing

Main supervisor: Arno Hänninen, University of Turku, Turku University Hospital, InFLAMES Flagship

Other supervisor(s): Saara Hämälistö, University of Turku

Doctoral researcher: Mohd Umar Tabrez

Pilot project description

Systemic lupus erythematosus (SLE) is a severe autoimmune disease with various clinical courses. In a prospective study, we combine clinical data and immune monitoring to investigating microbial triggers and trained immunity. This may reveal biomarkers for better prediction of organ involvement, activity flares and response to therapy.

Exosomes and other extracellular vesicles (EV) are a diverse population of nano/microparticles derived from various cells and involved in immune-cell crosstalk. EV may contain proinflammatory mediators, immune-stimulating miRNAs and material from dying cells including endogenous danger-associated molecular patterns (DAMP) such as nucleic acids and nucleoproteins to induce inflammasome activation and stimulation of interferons. EV have been implicated in SLE and RA, but technologies to analyze their content are rapidly progressing. We apply proteomics and transcriptomics to characterize their protein and miRNA content by mass-spectrometry and qPCR and possibly on single EV-level using microfluidics techniques.

To discover new mechanisms of immune pathology in SLE we compare 16S-RNA -encoding DNA in circulating low-density granulocytes (LDG) and neutrophils in patients and healthy volunteers. Proposedly, barrier breach in mucosal surfaces increases presence of bacterial DNA in circulating LDG and neutrophils. By next-generation sequencing of 16SRNA -encoding bacterial DNA we aim to identify microbes and annotate them on genus/species level to predict their origin either from the gut or other surfaces and their role in immune-cell activation.

Using single-cell transcriptomics we simultaneously profile leukocyte subsets for their response to microbial TLR-ligands. This allows to parallel the abovementioned investigations with studying variation in “trained immunity” in SLE development.

This study takes place in University of Turku, Turku Biosciences and the diagnostic laboratory and rheumatology unit of Turku university hospital.

Keywords: Systemic lupus erythematosus (SLE); biomarkers; Extracellular vesicles; trained immunity; single cell RNA sequencing; 16S RNA parallel sequencing.

Main supervisor: Arno Hänninen, University of Turku, Turku University Hospital, InFLAMES Flagship

Other supervisor(s): Tapio Lönnberg, Turku Bioscience Centre and InFLAMES Flagship,
University of Turku
https://bioscience.fi/research/single-cell-genomics-immunology/profile/

Doctoral researcher: Itishree Singh

Pilot project description

As the core of a clinical follow-up study, we profile systemic lupus erythematosus (SLE) patients’ immune system by novel approaches. SLE is a systemic autoimmune disease with great variation in its clinical course. New biomarkers are required for better prediction of each individual’s risk of developing organ involvement and activity bursts (flares). SLE often leads to coronary heart disease, chronic lung disease, chronic kidney disease, skin and joint involvement and other morbidities.

Myeloid cells and B-lymphocytes have important roles in SLE pathogenesis. Myeloid cells secrete mediators and B-cells produce autoantibodies to induce inflammation. We use a broad panel of immunological tests to profile B-cell subsets and monitor neutrophil and monocyte phenotypes and activity, and determine the presence of microorganisms in white blood cells. Our hypothesis is that microorganisms derived from the gut or mucosal surfaces act as triggers of inflammation and autoantigen release. We further hypothesize that individual differences in immune receptor signaling due to intrinsic factors and environmental adaptation determine this activity, reflected on the level of individual gene expression. Therefore, we study individual variation in monocytes’ and B-cells’ responses to microbial encounters using mimics of microbial encounters. To identify individual tuning of immune response on the level of single genes, we study each individual’s myeloid cells and B-lymphocytes using single-cell transcriptomics (scRNA-seq) and combine it with extended immunological profiling and clinical data. This may lead to identification of novel biomarkers related to individual variance in immune responsiveness and help stratify SLE patients for justification of individual treatment decisions.

This study involves University of Turku, Turku Biosciences and the diagnostic laboratory and rheumatology unit of Turku university hospital. Both supervisors are affiliated in InFLAMES and collaborate in this project.

Key words: Systemic lupus erythematosus (SLE); novel biomarkers for prediction; myeloid cells and B–lymphocytes; TLR–ligands; single–cell RNA sequencing; 16S RNA sequencing

Main supervisor: Johanna Ivaska, University of Turku, joivaska@utu.fi,
www.ivaskalab.utu.fi

Other supervisor(s): Guillaume Jacquemet, Åbo Akademi University,
guillaume.jacquemet@abo.fi: www.cellmig.org

Doctoral researcher: Monika Vaitkevičiūtė

Pilot project description

Aim of the project. Explore immune cell control of cancer cell crossings of the vessel wall. Hypothesis: “Metastasis is influenced by the interaction between immune cells and cancer cells, along with the immune modulation of the endothelium”. Our previous findings indicate that the mechanisms driving cancer invasion into the extracellular matrix (ECM) also play a role in cancer dissemination through the vasculature. Yet, these studies were conducted in the absence of immune
cells. Prior research has established a significant connection between inflammation,
cancer, and the pivotal role of immune cells in fostering metastasis. Furthermore,
extensive research on immune cell trafficking and homing has detailed the essential
steps and molecules required for immune cell arrest, adhesion, and transmigration
across the endothelium to reach target tissues.
In contrast, the dynamics of immune cell interaction with circulating tumour cells
within the vasculature are still not fully understood. In this PhD project, we aim to
explore this area comprehensively by employing high-resolution imaging to examine the interactions between immune cells, cancer cells, and the endothelium within a microfluidic system. Our preliminary findings reveal a notable diversity in how cancer cells and different types of immune cells (monocytes and neutrophils) interact with the endothelium. Furthermore, our data suggest that a normal, confluent endothelium
presents a molecularly varied landscape, with areas that either permit or resist interaction with immune and cancer cells. We hypothesize that immune cells, along
with secreted inflammatory cytokines, significantly influence cancer cell-endothelium interactions, potentially controlling metastasis. This project utilizes our established microfluidics setup, high-resolution live microscopy, deep learning algorithms for precise tracking and quantification of cell interactions, and an innovative synthetic biology approach to identify, isolate, and analyze the endothelial cells and immune cells interacting with cancer cells. With these complementary approaches, we will identify how 1) immune cells modulate cancer-cell–endothelium interaction and transmigration & 2) the role of the immune cells in making the vascular border permissive to extravasation.

Key words: Circulating Immune cells, Circulating cancer cells, endothelium, cell-cell crosstalk, cancer immunology, metastasis

Main supervisor: Sirpa Jalkanen, Director, InFLAMES Flagship

Other supervisor(s): Adj Prof. Maija Hollmén, Medicity Research Facility and InFLAMES Flagship https://hollmenlab.com/

Doctoral researcher: Reshmi Suresh

Pilot project description

We are interested in those multiple ways cancer modifies our immune system for boosting its own growth and spread. The project is based on our recent finding that breast cancer causes significant changes in the draining lymph nodes, which promote their metastasis. Using single cell sequencing of metastatic lymph nodes of breast cancer patients, we have found several immune-related hit molecules, the expression of which is drastically changed in metastatic lymph nodes when compared to non-metastatic ones. This project aims at analyzing 1) the expression of these hit molecules at the protein level in different breast cancer types, 2) association of their expression to the immune landscape of the tumors, 3) correlation of the expression to clinical parameters 4) whether the soluble forms of the selected hits can be used as diagnostic/prognostic biomarkers. The project is expected to provide new targets for diagnosing and preventing metastasis of cancer cells and the modulation of anti-tumor immunity. The project will be performed in MediCity at University of Turku in close collaboration with clinicians. The project utilizes unique human materials and several technologies such as multiplex immunohistochemistry and most modern imaging tools, flow cytometry, ELISA and bioinformatics.

Key words: lymphatics, immune landscape, cancer

Main supervisor: Sirpa Jalkanen, Director, InFLAMES Flagship

Other supervisor: PhD, Adjunct Professor (Docent) G. Yegutkin, , Medicity Research Laboratory and InFLAMES Flagship, University of Turku, gennady.yegutkin@utu.fi

Doctoral researcher: Samuel Svärd

Pilot project description

ATP and adenosine have emerged as important signaling molecules in various organs and tissues, including the eye. The discovery of adenosine as an immune checkpoint regulator in cancer has led to the development of novel therapeutic strategies targeting the ATP-adenosine pathway in multiple clinical trials and preclinical models (Yegutkin & Boison 2022, DOI: https://doi.org/10.1124/pharmrev.121.000528). However, current knowledge on metabolic pathways governing the duration and magnitude of purinergic signaling in the mammalian eye is incompletely understood.
Microglia are the main resident macrophages in the central nervous system. These immune cells maintain brain and retinal homeostasis by monitoring and scavenging dying cells, responding to pathogenic stimuli via the release of interleukin-1β, TNF-α and other cytokines, and also by inactivating proinflammatory ATP to anti-inflammatory and neuroprotective adenosine through the CD39-CD73 axis. This rationale leads us to the hypothesis that microglia, neurons, and other retinal cells are characterized by unique purinergic signatures and different metabolic demands. The relevance of purinergic pathway in microglial activity will be investigated in the experimental animal models of the neonatal hypoxic-ischemic encephalopathy, oxygen-induced retinopathy, as well as in mice with altered melanocyte development and retinal dysfunction due to a single nucleotide mutation in the microphthalmia-associated transcription factor (MITF) gene. This project aims at analyzing 1) the expression levels of key purinergic ectoenzymes and receptors in retinal microglial cells, 2) the purinergic mechanisms involved in the transition of microglial cells from a quiescent state to the activated disease-associated phenotype, 3) the spatial dynamics and metabolic crosstalk between microglia, retinal vasculature, neurons, and other components of the neurovascular unit, and 4) the role of microglia-derived ATP and adenosine in ocular inflammation and progression of neurodegenerative diseases. To accomplish these tasks, we will use a three-dimensional multiplexed imaging, in situ enzyme histochemistry, flow cytometric analysis, scanning electron microscopy, and electroretinography, in combination with single cell transcriptomics of retinal cells. Overall, this project will provide a holistic view of purine metabolism and signaling in the mammalian eye and on this basis, allow to establish a link between ocular adenosine homeostasis, inflammation, and other vision abnormalities.

Key words: Microglia, retinal inflammation, ocular diseases, CD39, ATP, adenosine

Main supervisor: M.D., Ph.D. Ilkka Julkunen, University of Turku, InFLAMES Research Flagship, ilkka.julkunen@utu.fi

Other supervisor(s):  Pekka Kolehmainen, Institute of Biomedicine, University of Turku, pekka.j.kolehmainen@utu.fi

PhD, Adjunct professor, Laura Kakkola, Institute of  Biomedicine, University of Turku

Doctoral researcher: Sophie Winter

Pilot project description

Avian influenza A viruses (AIV) form a significant pandemic threat for animal and human health. In 2023 Finland suffered from a devastating wild bird and fur animal epidemic that led to the death of thousands of seagulls and water birds as well as culling of more than 500 000 fur animals. Personnel at fur farms, veterinarians and laboratory workers were exposed to circulating avian influenza strains, but no human cases were identified in Finland. EU has purchased 2 million doses of H5N1 type AIV vaccine of which 20 000 doses were intended for human use in Finland. Finland has started public vaccinations with AIV vaccine, with target groups being fur farm workers, poultry industry workers, veterinarians and laboratory workers who are exposed to avian influenza virus in their work. Finnish Institute for Health and Welfare (THL) together with the research group of Ilkka Julkunen at the University of Turku has initiated a clinical follow-up trial on analyzing adaptive immunity induced by AIV vaccine.

The project includes an experimental part in mice with DelSiTech Ltd. (Turku) to study the immunogenicity of the commercial AIV vaccine compared to our own Finnish type AIV H5 protein antigens. The major emphasis is on DelSiTech silica matrix-based slow release of viral antigens that based on preliminary data enhances immune responses after vaccination. The clinical part started in August 2024 and it includes the collection of blood samples before and after a two-dose AIV vaccine regimen. Humoral and cell-mediated immunity will be analyzed with the most modern laboratory methods. The project includes work in the BSL-3 facility of the University of Turku, study visits to DelSiTech and THL (Helsinki), and the project provides the Ph.D. student excellent experience in immunological methods and BSL-3 work. This project is globally the first one to analyze adaptive immunity induced by current avian influenza vaccine and thus the public health impact of the project is highly significant.

Key words: Avian influenza, vaccine, humoral immunity, cell-mediated immunity, clinical trial

Main supervisor: Laura Kakkola, Institute of Biomedicine, University of Turku

Other supervisor(s): Ilkka Julkunen, Institute of Biomedicine, University of Turku

Doctoral researcher: Beda Anttila

Pilot project description

The aim of this project is to reveal the innate immune responses that seasonal influenza viruses A/H1N1pdm09 from years 2009 to 2024 and avian influenza viruses from years 2022-2023 induce or inhibit in infected cells. With this information, we aim to analyze the mechanisms of adaptation of influenza viruses to replication in human cells. The role of the major viral innate immune repressor, NS1, in adapted influenza viruses will be studied in detail. We expect to find differences in the adapted influenza viruses and in the ability of NS1 proteins to inhibit innate immune pathways. Further, the hemagglutin directed antibodies will be analyzed for a possible cross-reactivity in animals and humans. This project will give significant information on the immune responses and adaptation process of influenza viruses, especially of avian influenza viruses currently causing a global threat.

The project will be conducted in the Institute of Biomedicine, Faculty of Medicine. In the project you will use live pathogenic viruses and cloned virus genes, set up novel mass cytometry methods and use cell culture, elisa, RT-qPCR, protein production methods and data analysis (GraphPad, Excel, FlowJo, etc.). You will gain specific expertise to work in biosafety level 3 laboratory, the skill that is directly transferable to the e.g. clean room work in pharmaceutical companies. The successful candidate has to be able to work with pathogenic viruses in biosafety level 3 laboratory, i.e. passing of thorough health check and official security clearance is required.

Key words: influenza virus, avian influenza, innate immunity

Main supervisor: prof. Juhani Knuuti, MD, PhD, Turku PET Centre, University of Turku, juhani.knuuti@utu.fi

Research group website: www.pet.fi also https://www.syslife.fi/research/#Theme1

Other supervisor(s): Dr David E Molnar, MD, PhD, Turku PET Centre, University of Turku and Department of Molecular and Clinical Medicine, University of Gothenburg, demolnar@yahoo.com

Doctoral researcher: Erika Saari

Pilot project description

Inflammation in the vessel wall and the surrounding adipose tissue (EAT) is key to the process of atherosclerosis. In-vivo positron-emission tomography (PET) and computed tomography (CT) offer potent methods of visualizing and gauging inflammatory activity in EAT. CT can measure the changes in the radiodensity of EAT. PET can directly measure the blood flow and visualize activated inflammatory cells in EAT. Currently, most of the knowledge is based on whole EAT while pericoronary EAT, that is believed to be the key player in atherosclerosis, has earlier required laborious manual work and therefore results in large populations are missing.

The aims of this project are to 1) apply the automatic image EAT analysis method recently developed by David Molnar in Gothenburg to pericoronary EAT analysis of an existing Turku cardiac PET/CT image registry data (nearly 3000 patients with clinical data, detailed CT and PET imaging and outcome data), 2) to apply the method also to SCAPIS study population (30 000 subjects in Sweden with cardiac CT), and 3) to study the feasibility of novel inflammatory PET tracer (F-18-folate) in detecting pericoronary inflammation in prospective study of patients.

Hypotheses: The main hypothesis is that inflammatory activity in early atherosclerotic lesions leads to migration of inflammatory cells to the surrounding tissue. Specific hypotheses are: a) changes in pericoronary EAT density can be measured very precisely in the 3D volume, localizing focal points of inflammatory activity b) changes in the density, perfusion activated inflammatory cells of the EAT is associated with the plaque characteristics.

Scientific novelty: The developed knowledge of pericoronary EAT in the population and clinical patients, representing the largest databases of high-quality images up to date, will enable more precise measurements of pericoronary inflammation in-vivo. The combination of morphological findings on CT to perfusion and inflammation on PET, will further enhance identification of dangerous inflammation associated with unstable plaques and coronary events.

Clinical utility: The detection through non-invasive CT and PET image analysis of early inflammatory changes in coronary atherosclerosis has the potential to improve both diagnostics and treatment selection for millions of patients world-wide.

Key word: Pericoronary inflammation, AI, computed tomography, PET, atherosclerosis

Main supervisor: Professor Mika Kortelainen, University of Turku and Finnish Institute for Health and Welfare (THL), mika.kortelainen@utu.fi

Other supervisor(s): Professor of Practice Juha Laine, University of Turku and Roche

Doctoral researcher: Matti Rajala

Pilot project description

The rising costs of pharmaceuticals, particularly biological medicines, have become a major concern in Finland. In 2022, pharmaceutical expenditure reached approximately 3.8 billion euros, with biologics—such as monoclonal antibodies for autoimmune diseases and cancer immunotherapies—playing a significant role. As large share of biologics modify the immune system, they are vital but costly therapies, creating concerns about healthcare affordability and access. In response, Finland introduced the generic substitution of biological medicines in 2024, a policy intended to increase competition and reduce prices by allowing biosimilars—lower-cost alternatives to original biologics—to be automatically substituted at pharmacies.
This research aims to evaluate the economic and clinical impacts of this policy, with a particular focus on immunological treatments. It will seek to answer three key questions: (1) How has generic substitution affected the prices and expenditures on biologics, especially within immunological diseases? (2) What shifts have occurred in market dynamics, including the availability of innovative biologics and their biosimilars and changes in market concentration, particularly in immunological therapies? (3) How does non-medical switching from original biologics to biosimilars affect healthcare resource utilization (HCRU) and patient outcomes in immunological conditions?
By utilizing quasi-experimental research designs and analyzing real-world data, this study will assess the broader impacts of pharmaceutical policies on both the accessibility and quality of immunological treatments. The findings will contribute important insights into the effectiveness of cost-containment strategies, guiding future policy decisions to improve the affordability and efficacy of immunological therapies. Ultimately, this research has the potential to enhance patient outcomes while advancing the future of immunology by promoting wider access to biosimilar treatments.

Key words: Biological drugs, biosimilars, immunological treatment, price competition, cost-effectiveness, economic evaluation

Main supervisor: Riitta Lahesmaa, Professor of Systems Immunology, Director, Turku Bioscience Centre, rilahes (at) utu.fi

Research group website: https://bioscience.fi/research/molecular-systems-immunology/profile/

Other supervisors:

Tanja Buchacher, PhD, Senior Researcher, email address, tanja.buchacher@utu.fi; https://bioscience.fi/research/molecular-systems-immunology/profile/;

Ubaid Kalim, docent, senior researcher, Turku Bioscience Centre

Doctoral researcher: Gopika Jayan Menon

Pilot project description

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing beta cells of pancreas leading to life-long insulin dependency. Better understanding of heterogeneity of the disease process and its early detection in susceptible children are critical to enable timely prevention, treatment and recruitment of at-risk subjects for clinical intervention studies.

This project aims to 1) characterize in detail changes in immune cells associated with distinct stages during progression to T1D and 2) understand the basis for the considerable heterogeneity in the rate of progression to clinical T1D.

The changes will be identified using longitudinal blood samples from unique cohorts covering time from birth to developing clinical disease, and their matched controls, using experimental and computational methods and work-flows already optimized for these studies in our group (Buchacher et al. 2023 doi: 10.1016/j.celrep.2023.113469), Starskaia et al. (2024) doi: 10.1038/s41467-024-47918-w., Suomi et al. doi: 10.1016/j.ebiom.2023.104625.). The study employs cutting-edge methods including single-cell RNA-seq, mass cytometry and spectral flow cytometry.

The results are expected to provide new insights into distinct disease pathways underlying the heterogeneity and endotypes of T1D, means for early detection of the disease process and for timely intervention, and provide basis for developing new strategies for novel targeted therapies for T1D.

The PhD training provides in-depth understanding of the central principles in the control of human immune response. A vantage point for cutting-edge research and excellent opportunities for learning from leaders in the field both in academia and industry are offered as the Lahesmaa group actively contributes to research in large international private-public consortia with significant involvement from leading Pharma companies in the area of T1D.

Key words: Human immune response, T cells, immune mediated diseases, type 1 diabetes, early diagnosis, disease modifying therapies

Main supervisor: Riitta Lahesmaa, MD, PhD, Professor of Systems Immunology, Director, Turku Bioscience Centre and InFLAMES Flagship

Other supervisor(s): Tanja Buchacher, PhD, Senior Researcher
https://bioscience.fi/research/molecular-systems-immunology/profile/

Doctoral researcher: Nikita Kumar

Pilot project description

Regulatory T cells (Treg) are vital for maintaining immune tolerance and immune homeostasis. Modulating their function has significant therapeutic potential for controlling human autoimmune and inflammatory diseases as well as cancer. In spite of advances in Treg cell biology, the molecular mechanisms of human Treg differentiation and function are incompletely understood.

The Lahesmaa group identifies new ways to control Treg. We have discovered novel factors upregulated in Tregs. This project will study the role of two such factors in regulating Treg differentiation and function. We have already shown they both influence expression of FOXP3, a key transcription factor defining Treg and that one of them is upregulated in tumor infiltrating lymphocytes. These along with our other preliminary data demonstrate feasibility and notably highlight these two factors as highly interesting novel regulators of Treg response.

The work is done in Lahesmaa lab at Turku Bioscience Centre with an excellent research infrastructure. The doctoral researcher will study clinical samples from patients with immune mediated diseases and cancer and use a range of cutting-edge methods in molecular and cellular biology, epigenetics and bioinformatics including RNAi/LNA mediated silencing/CRISPR-Cas9 gene editing combined with single-cell RNA-seq, mass cytometry and proteomics. All the methods are optimized in the group as reported (Buchacher et al. 2023 doi: 10.1016/j.celrep.2023.113469; Shetty et al. 2022 doi: 10.1093/nar/gkac256; Khan et al. 2022 doi: 10.1016/j.crimmu.2020.02.001; Andrabi et al. 2023 doi: 10.1016/j.imlet.2023.09.001).

The results are expected to provide new insights and basis for developing new strategies for novel targeted therapies for autoimmune and inflammatory diseases and cancer.

The PhD training provides the candidate with in-depth understanding of central principles in the control of human immune response – valuable for a career both in industry and academia.

Key words: Human immune response, T cells, regulatory T cells, immune mediated diseases

Main supervisor: professor Leo Lahti, Department of Computing, University of Turku, leo.lahti@utu.fi | datascience.utu.fi

Other supervisors: professor Paulina Salminen, Department of Surgery, University of Turku and Division of Digestive Surgery and Urology, Turku University Hospital paulina.salminen@tyks.fi
Dr. Eveliina Munukka, Turku Clinical Microbiome bank, Dept. Clinical Microbiology, University Hospital of Turku and Institute of Biomedicine, University of Turku, laevmu@utu.fi,

Doctoral researcher: Vilhelm Suksi

Pilot project description

Acute appendicitis is one of the most common in infections worldwide that has been traditionally treated by emergency surgery. Currently, it is accepted both epidemiologically and clinically that two forms of this infection exist, namely complicated and uncomplicated appendicitis, which also suggests different pathophysiology, microbial etiology and host response. Previously the translational study consortium (Microbiology APPendicitis ACuta) has shown that appendiceal microbiota between uncomplicated and complicated acute appendicitis have different microbiome profiles further supporting the disconnection between these two different forms of acute appendicitis. Majority of patients with uncomplicated acute appendicitis can be treated with antibiotics alone or even without any treatment (placebo). However, our immunological understanding of the differences between these subtypes remains limited. This project will examine the hypothesis that besides the different appendiceal microbiome profile, also the inflammatory profiles between previously mentioned two appendicitis groups differ. It will take advantage of the latest advances in microbiome data science and further customize these methods for metagenome-metabolome data integration to support applications in immunology. Host response during the acute appendicitis will then be evaluated by computationally integrating unique metagenomic and metabolomic data from appendix and serum. This will enhance the holistic understanding of the relevant inflammational processes and to generate validated microbiome biomarkers for assessing individual risk for developing recurrent appendicitis after successful antibiotic or symptomatic treatment. The project will be carried out at the Department of Computing, University of Turku in close collaboration with Turku University Hospital.

Key words: appendicitis, inflammation, metabolomics, metagenomics, multi-omics, data science

Main supervisor: Urpo Lamminmäki, PhD, prof., Department of Life Technologies / Biotechnology, University of Turku
https://antibodyengineering.utu.fi/

Other supervisor(s):
Bryce Nelson, PhD, Head of Antibody Engineering, Orion Pharma Oy, Turku, bryce.nelson@orionpharma.com
https://www.orion.fi/
Antti Kulmala, PhD, Senior Scientist, Orion Pharma Oy, Turku,
antti.kulmala@orionpharma.com,
https://www.orion.fi/

Doctoral researcher: Adeesha Herath Mudiyanselage

Pilot project description

This collaborative project between Dept. of Life Technologies/UTU and Orion Oy aims to establish aversatile technology platform to advance development of next-generation immunotherapeutics. With >170 clinically approved antibody drugs, antibodies stand as a major triumph in modern medicine. Today, scientists are striving to pioneer immunotherapies based on increasingly intricate designs like bispecific antibodies, posing significant challenges in their development. Single heavy chain variable domains (VHHs), presenting the smallest antigen binding units from immunoglobulins, hold great potential as simple molecular components for crafting future biotherapeutics.

Project’s key goals are: i) to create of a universal molecular library for rapid discovery of novel VHHs to various disease targets, ii) to demonstrate benefits of these VHHs in intricate antibody designs. As the VHH framework is extracted from its natural environment within the intact antibody, it needs to be optimized for biophysical characteristics, such as stability and solubility. Here, an iterative engineering process using bioinformatics-based structural design and directed evolution is applied to explore different solutions to create a human VHH domain with superior biophysical characteristics, followed by diversification of the binding site by emulating natural immunoglobulin diversity.

Resulting preliminary VHH libraries will be filtered with phage and mammalian cell display techniques to eliminate potentially problematic protein variants. The final highly diverse phage display VHH library will be validated by selecting VHH binders to relevant immunotherapy targets, incorporating the VHHs in different bi- and multispecific antibody designs, followed by careful analysis of their biochemical/-physical and biological properties. The technology platform developed here is expected have a considerable impact on the possibilities to investigate and develop next-generation immunotherapeutics in Finland.

Key words: Antibody engineering, Antibody library, Next-generation biotherapeutics, VHH

Main supervisor: Professor Urpo Lamminmäki, Department of Life Technologies, Biotechnology Unit,
urplammi@utu.fi, https://antibodyengineering.utu.fi/

Other supervisor(s): PhD, group leader Emilia Peuhu, Institute of Biomedicine, Cancer Laboratory FICAN West,
emilia.peuhu@utu.fi, https://peuhulab.utu.fi/
PhD, Senior researcher Eeva-Christine Brockmann, Department of Life Technologies, Biotechnology
Unit, eechbr@utu.fi, https://antibodyengineering.utu.fi/

Doctoral researcher: Susanna Lammi

Pilot project description

The project seeks to develop a practical approach for generating ultra-stable recombinant antibody molecules with potential applications in diagnostic assays and biologic drugs. This approach involves engineering a generic structural modification near the antigen-binding site of antibodies to enhance their stability. Using the anti-Her2 breast cancer drug Trastuzumab as a model, we have demonstrated that this method significantly improves the thermal stability of the antibody, and appears to result in a more rigid binding site.
This increased thermal stability and rigidity of the antigen-binding domains can offer several advantages, including reduced aggregation, improved binding specificity, faster binding kinetics as well as better durability and manufacturability. These attributes make the concept promising for the development of advanced antibodies for challenging diagnostic and therapeutic purposes.
The project’s primary goals are: i) To complete the ongoing proof-of-concept study, which highlights the advantages of this approach in developing different types of Her2-targeting antibody constructs. ii) To establish and validate a technology platform for the efficient discovery of ultra-stable antibodies against novel protein targets.
The research will be conducted in the Antibody Engineering group at the Dept. of Life Technologies, which has extensive experience in this field. Cell-based studied will be carried out in Dr. Peuhu’s laboratory in Institute of Biomedicine. The project will utilize a wide range of technologies, including phage display, mammalian cell display, cell sorting, next-generation sequencing, cell culture and techniques for recombinant protein expression, purification, and characterization. These resources are either available onsite or accessible through the Turku BioCampus core facilities.

Key words: Antibody engineering, Antibody library, Mammalian cell display, Phage display, Protein stability

Main supervisor: Adj. Professor Janne Leivo, University of Turku, jpleiv@utu.fi,

Other supervisor(s): PhD Etvi Juntunen, Olo Health, etvi@olo.health

Doctoral researcher: Ida Bäckström

Pilot project description

Estradiol (E2), the most potent female hormone, is crucial in numerous human physiological processes. The accurate and rapid detection of E2 is essential not only for medical diagnostics but is increasingly relevant for personalized health monitoring. Immunochemical methods are routinely used to detect E2 mainly due to their cost-effectiveness and simple sample handling. Despite advancements in immunoassays for measuring circulating E2, issues related to the poor sensitivity and reproducibility of the assays persist for routine clinical use and advanced epidemiologic studies. We have previously shown that the antibody generation conditions of phage display selection of synthetic antibody libraries can be controlled to direct the conditions to stabilize existing antibody-antigen interactions. These immunocomplexes (ICs) have proven to bring significant versatility and additional sensitivity to the downstream applications of the antibodies, particularly for small molecule analytes. The unique binding properties of the IC antibodies enable the development of simple and cost-efficient immunoassays, which have previously been developed into diagnostic products by the Division of Biotechnology at the University of Turku.
This ImmuDocs project is done at the interface of academia and industry with clear and practical relevance at the end of the project. The aim is to mature the novel IC antibodies into simple and analytically powerful assay concepts for the detection of circulatory E2. More specifically, the objectives and tasks for the
ImmuDocs project are:
1) Engineer and affinity mature the anti-IC antibodies for increased affinity and stability with site-directed
mutagenesis and phage display.
2) With industry support, design and develop a novel non-competitive lateral-flow rapid test for highsensitivity
detection of E2.
3) Evaluate and compare the clinical performance of the novel assays with commercially available ultrasensitive
assays (Quanterix Simoa HD-X).

Key words: Immunodiagnostics, immunocomplex, personalized health, antibody, rapid test, hormone

Main supervisor: Adj. Professor Tapio Lönnberg, Turku Bioscience Centre and InFLAMES Flagship Centre, University of Turku,
taplon@utu.fi, https://bioscience.fi/research/single-cell-genomics-immunology/profile/

Other supervisor(s): PhD Lea Mikkola, Turku Bioscience Centre and InFLAMES Flagship Centre, University of Turku,
lea.mikkola@utu.fi

Doctoral researcher: Sara Metso

Pilot project description

Osteoarthritis (OA) affects more than 500 million people, causing a significant and growing socioeconomic burden. Dissatisfaction with current approaches for symptom relief is common among patients, and better understanding of mechanisms of OA pain is urgently needed. Recent studies have revealed that OA is not a purely degenerative disease, but also influenced by inflammatory mechanisms. Importantly, while the correlation of pain with radiological features is poor, pain is most pronounced in the inflammatory subgroup of OA patients.
There is a gap in knowledge of how neuro-immune interactions in the affected joints regulate OA pain. However, it is known that pain sensation is possible from the synovium, ligamentum teres, and the fibrous joint capsule, as all of them have free nerve endings and immune cells (e.g. macrophages and mast cells) surrounding them. Preclinical and clinical data demonstrate involvement of immune cells in modulation of chronic peripheral neuropathic pain and OA-related pain. Hence, identification of immune mediators of pain in these tissues can provide new druggable targets.
In this project we will utilize OA patient samples uniquely available to us after hip replacement surgeries. We aim to characterize neuro-immune interactions in the key tissues of the hip joint using state-of-the-art singlecell and spatial omics, imaging techniques, and established in vivo and ex vivo models. Our aims are 1) to map the neuro-immune landscape in high resolution in ligamentum teres and the fibrous joint capsule while using the synovium as a positive control; 2) to define the pivotal immune cell populations and gene signatures that regulate pain response in hip OA patients; and 3) to characterize molecular pathways mediating neuroimmune interactions using pharmacological and genetic tools in co-cultures of sensory neurons with immune cells and rodent knee OA models.

Key words: neuro-immune interactions, innate immunity, osteoarthritis, pain

Main supervisor: Adj. Professor Tapio Lönnberg, Turku Bioscience Centre and InFLAMES Flagship Centre, University of Turku
taplon@utu.fi, https://bioscience.fi/research/single-cell-genomics-immunology/profile/

Other supervisor(s): Associate Professor Pekka Ruusuvuori, Institute of Biomedicine, University of Turku pekka.ruusuvuori@utu.fi
https://ruusuvuorilab.utu.fi/
PhD Lea Mikkola, Turku Bioscience Centre and InFLAMES Flagship Centre, University of Turku
lea.mikkola@utu.fi

Doctoral researcher: Emilie Rydgren

Pilot project description

Rheumatoid arthritis (RA) and osteoarthritis (OA) are relatively common debilitating diseases with no curative treatments. In RA, disease progression is linked with chronic inflammation of the synovial membrane, mediated by pathogenic T cells. The phenotypes of these cells have been recently elucidated with single-cell sequencing by us and others. However, to be able to translate these results into candidates for drug targets, more information is needed about the tissue context and cellular interactions of the diseaseassociated cells. While OA has traditionally been viewed as a purely degenerative disease, it is becoming evident that it can also be driven by inflammatory mechanisms. Notably, OA can develop in both weight-bearing and nonweight- bearing joints and synovial inflammation can precede visible bone damage and is associated with pain severity. Furthermore, there is significant interindividual variability of the synovial immune infiltrates, suggesting a need for more informed patient stratification. The understanding of the disease processes in RA and OA has been hampered by lack of high content analysis tools which preserve tissue context. In this project we will tackle this challenge with novel high-resolution spatial transcriptomics and proteomics methods in combination with 3D histology. Our project aims at 1) characterising the immune cell infiltrates in synovial tissues from patients with RA and OA, 2) determining their interactions with the stromal microenvironment, and 3) identifying clinically measurable peripheral biomarkers for synovial inflammatory processes. We are well positioned to reach these aims, having access to advanced research methods, an established patient cohort, and a strong network of collaborators with versatile expertise. The project will provide unprecedentedly detailed information on the mechanisms that sustain chronic synovial inflammation, offering possibilities for more efficient diagnostics and therapies.

Key words: Rheumatoid arthritis, osteoarthritis, T cell, single-cell, spatial transcriptomics, inflammation.

Main supervisor: Pieta Mattila, PhD, Title of Docent, InFLAMES research Flagship, Institute of Biomedicine, University of Turku

Group website: https://mattilalab.utu.fi/

Other supervisor(s): Saara Hämälistö, PhD, FICAN West, Institute of Biomedicine, University of Turku

Group website: https://hamalistolab.utu.fi/

Doctoral researcher: Sikha Valiyapurakkalthottupura Raghuthaman

Pilot project description

B cells form a vital branch of the adaptive immune system by mounting antibody responses and immunological memory. Antigen binding to the B cell antigen receptor (BCR) triggers a branched signaling network with complex cell biological outcomes enabling the launch of antibody responses. In this project, based on our strong ongoing research, we focus on the roles of the secreted extracellular vesicles (EVs), together with intracellular lysosomes, as novel regulators of B cell activation and immune response.

A) B cell-derived EVs (B-EVs) in modulation of the immune system. Hypothesis: Via robust secretion of EVs, B cells modulate their cellular environment and immunological status.

EVs have lately emerged as a powerful layer of intercellular communication by transmitting biological cargo, like enzymes, regulatory RNAs and lipids, to the recipient cells. Our ongoing work has revealed highly interesting characteristics of B-EVs that the candidate will study further focusing on the lead molecules identified in the proteomic and transcriptomic profiling. By injecting labelled B-EVs into the mouse, they will examine the targeting of B-EVs in tissues and the effects the EVs induce in the recipient cells, the homeostasis of the immune system, and mounting of the immune response.

B) Lysosomes in B cell activation. Hypothesis: Lysosomes play a previously unrecognized role in regulating early events in B cell activation.

In our ongoing research we have found that inhibition of lysosomes strongly impairs B cell activation. The candidate will participate in research unveiling the molecular mechanisms of this highly interesting acute role of lysosomes, and its functional impact in, e.g. vesicle release and antigen presentation.

This project, at the Institute of Biomedicine, University of Turku, utilizes e.g. advanced microscopy and flow cytometry and, as model systems, cultured cells and mice. Two research lines mitigate the risk and provide flexibility.

Key words: B cells, lymphocyte activation, antibody response, antigen signaling, lysosomes, extracellular vesicles

Main supervisor: Pieta Mattila, PhD, Title of Docent, InFLAMES research flagship, Institute of Biomedicine, University of Turku, Email: pieta.mattila@utu.fi

Group website: https://mattilalab.utu.fi/

Other supervisor(s): Otto Kauko, MD PhD, Turku Bioscience Centre, University of Turku & Åbo Akademi, Email: otkauko@utu.fi

Group website: https://bioscience.fi/research/cancer-proteomics/profile/

Doctoral researcher: Shahrzad Bolouri

Pilot project description

B cells form a vital branch of the adaptive immune system by mounting antibody responses and immunological memory. At the same time, B cells serve as antigen (Ag) presenting cells to activate other immune cells, the function that is emphasized, for example, in autoimmune diseases. Here, we focus on unveiling the role of septin cytoskeleton in Ag processing, the key step in peptide-Ag presentation and immunity.

A) Characterizing the role of Septin7 in Ag processing and peptide presentation, using Septin7-deficient (Sept7-cKO) mice.

Our ongoing work has revealed highly interesting roles for septins in B cell activation, including functions of endolysosomal vesicles that process internalized Ag for presentation. The project will utilize the B cell conditional Sept7-cKO mouse model that we have generated, which downregulates all major oligomerically operating septin family members in B cells. We will mechanistically examine the defected Ag-presentation with a focus on the molecular alterations in Ag-processing intracellular vesicles.

B) Revealing the role of septins in human B cells.

Our preliminary data on mouse B cells aligns well with the literature defining septins as important regulators of endolysosomal trafficking and maturation in other cell types. Here, we will study the role of septin cytoskeleton in human B cell activation and Ag-presentation functionally, using a pan-septin inhibitor in primary cells and by silencing Sept7 and Sept9 in human B cell lines (Sept9 is suggested as the predominant septin family member in human cells). Also, the interactomes of both Sept7 and Sept9 will be examined.

Together, we aim to reveal how septins regulate Ag-processing and presentation via their regulatory function on endolysosomal compartments, both in mice and human. This project, based on our ongoing research at the Institute of Biomedicine, University of Turku, utilizes e.g. advanced microscopy and proteomics, cultured and primary cells, as well as an existing mouse model.

Key words: B cells, lymphocyte activation, antigen presentation, endolysosomes, Septins, proteomics

Main supervisor: Associate Professor Alexander Mildner, PhD, Department of
Biomedicine, InFLAMES Flagship
https://mildnerlab.utu.fi/

Other supervisor(s): Akira Takeda, PhD, Department on Biomedicine, InFLAMES Flagship
https://takedalab.utu.fi/

Doctoral researcher: Miriam Langguth

Pilot project description

Tissue macrophages (M φ) have distinct functions based on their environment. For instance, lung alveolar Mφs (AMs) eliminate surfactant lipids. AMs acquire this ability from lung epithelial cells that release GM-CSF, which activates the lipid-handling transcription factor PPARg. However, PPARg comes in two isoforms, and previous studies have shown that PPARg2 is mainly found in adipocytes while PPARg1 is expressed in many cell types. In contrary, we found that PPARg2 and not PPARg1 is the primary isoform that grants lipid-degrading abilities to AMs, while other Mφs, such as splenic Mφs, only express PPARg1 (PMID: 36112694). Interestingly, a recent study suggests that the development of spleen Mφs is blocked in PPARg-deficient mice (PMID: 33765133). These results indicate that PPARg1 and PPARg2 are differentially regulated and play different roles in various Mφ subsets. We therefore speculate that PPARg2 is primarily involved in AMs lipid degradation, whilePPARg1 regulates a different set of target genes that are crucial for spleen Mφ differentiation. Since PPARg has emerged as a promising target in a multitude of pathologies like diabetes or pulmonary alveolar proteinosis, a better understanding of the isoform-specific functions and regulation of PPARg might contribute to develop more effective and targeted treatments.

In this basic immunological project, we aim to unravel the regulation and function of the PPARg isoforms 1 and 2 in lung and spleen Mφs, which can provide meaningful insights for more targeted drug development. We will use epigenetics (ChIP-Seq, Cut&Run, ATAC-Seq), molecular analysis (RNA-Seq, scRNA-Seq), Immunoblotting and specific, established PPARg1 and PPARg2 knockout mouse models under steady state conditions to identify PPARg1 and 2 function and their specific target genes. The research will be conducted in the Mildner lab, Department of Biomedicine, BioCity. All molecular techniques are established.

Key words: innate immunity, macrophage, epigenetics, differentiation

Main supervisor: Teemu Niiranen, MD, PhD, Professor, Department of Internal Medicine, University of Turku
https://www.hypertensioncenter.org

Other supervisor(s): Joonatan Palmu, MD, PhD, Department of Internal Medicine, University of Turku, jjmpal@utu.fi
https://www.hypertensioncenter.org

Doctoral researcher: Hassan Diab

Pilot project description

This is a dry lab/computational position for a PhD student interested in computational biology and microbiome analysis. The suitable candidate has a background in biostatistics, medicine, bioinformatics, epidemiology, computer science, biology, or mathematics. Professor Teemu Niiranen’s group (Internal Medicine Unit, Department of Clinical Medicine) works on a wide range of topics with a current focus on multi-omics analysis in large-scale population cohorts.

This overarching goal of the current project is to elucidate the role of the gut microbiome as a risk factor for systemic inflammation and incident autoimmune disease. The current research will be performed using data from the nationwide, prospective FINRISK 2002 cohort.

In the year 2002, over N=7200 FINRISK 2002 participants underwent a health examination, blood sampling and stool sampling. The participants have been followed up for over 20 years for incident health events. The stool samples have later been sequenced using shotgun metagenome sequencing, allowing us to comprehensively assess the gut microbiome of the participants. In addition, a panel of 45 circulating cytokines, including pro-inflammatory interleukins, chemokines and growth factors, has been measured in a subsample of N=3000 participants.

Our specific aims are:
1) To assess the cross-sectional associations between the gut microbiome and circulating cytokines.
2) To examine the prospective links between baseline gut microbiome and incident rheumatic autoimmune
disease (e.g. rheumatoid arthritis, systemic inflammatory disease) over a 20-year follow-up.
3) To study the prospective associations between the gut microbiome and incident inflammatory bowel
disease (Crohn’s disease and ulcerative colitis) over a 20-year follow-up.

We hypothesize that we will be able to discover numerous microbial signatures that are related to inflammation and autoimmune disease. Manipulation of the gut microbiome could provide potential novel therapies for these disorders.

Key words: Gut microbiome, immunology, inflammatory autoimmune disease

Main supervisor: Adjunct Professor Elisa Närvä, FICAN West Cancer Centre and Institute of Biomedicine, University of Turku elisa.narva@utu.fi, Pluripotency & Cancer Laboratory:
https://narvalab.utu.fi/

Other supervisor(s): Adj. Professor Hollmén, MediCity Research Laboratory and
InFLAMES Flagship, University of Turku maijal@utu.fi, Tumor immunology and immunotherapy
Laboratory: https://hollmenlab.com/

Doctoral researcher: Sanne Sandelin

Pilot project description

The fields of immunology and stem cell science work closer than ever before to enable breakthroughs in therapies and diagnostics. Human pluripotent stem cells (hPSCs) can provide much-needed universal donor cells for immunotherapies and a source for the endless production of CAR T-cells, NK-cells, and macrophages, which are already in clinical trials. In addition, it has become clear that cancer-associated stem cells (CSCs) are vital in immune resistance and resulting treatment failure. This project will utilize and train new experts to use state-of-the-art stem cell and immunological techniques to reveal new aspects of tumor-associated immune cells. CSCs utilize developmental pathways to drive self-renewal and plasticity. The major challenge is that CSCs are highly heterogeneous and have multiple ways to protect themselves from the immune cells. These facts result in extreme difficulty in the diagnosis and therapy of CSCs. The AIM 1 is to reveal the immune landscape of CSCs from patient samples with CyTOF by utilizing our newly established stem cell panel combined with immunopanel. The multimarker analysis of CSCs and immune cells would be breaking new ground and increase the understanding of the crosstalk between these important cell types. Tumor-associated macrophages can express Clever-1 receptor increasing the immune tolerance of tumors. Currently, an antibody targeting Clever-1 is in clinical trials. Interestingly, recent findings show that mutations in the Clever-1 are associated with hyperferritinemia or can cause severe staphylococcus infections. However, functional studies on the identified Clever-1 mutation phenotypes are difficult due to very limited sample material. The AIM 2 is to generate patient-specific pluripotent stem cell lines via reprogramming technology and characterize how mutations alter the function of Clever-1 in stem cell-derived macrophages. Obtained data could reveal novel functions for Clever-1 and its importance for the immune system.

Key words: immune landscape, CyTOF, cancer stem cell, induced human pluripotent
stem cells, stem cell-derived macrophages, Clever-1

Main supervisor: Professor Matej Orešič, University of Turku, Turku Bioscience matej.oresic@utu.fi https://bioscience.fi/services/metabolomics/services/

Other supervisor(s): Docent Alex Dickens, University of Turku, Department of Chemistry and Turku Bioscience

PhD Matilda Kråkström, Turku Bioscience Centre

Doctoral researcher: Katja Salonen

Pilot project description

Recent advances in mass spectrometry (MS) have allowed for the identification of a novel forms of conjugations to structures such as bile acids (BAs) and N-acyl amides (NAAs). These metabolites were recently discovered by our collaborator Pieter Dorrestein1 and confirmed by the synthesis of over 2000 authentic standards. The role and function of these metabolites however remain unclear. BAs are known to regulate the host immune response and play a critical role in host microbe interactions. Indeed five of the synthetic conjugated BAs did increase IFN levels in naïve T-cells from mice. There is also evidence from our recent study that environmental contaminates such as perfluoroalkyl substances (PFAS) can regulate BA synthesis in utero2. NAAs are also immunomodulatory with the endocannabinoids known to be modulators of CB2 and PPAR
This project will utilize the developed analytical method for BAs and improve the existing NAA method to profile the novel conjugated BAs and NAAs in the INITALISE EU project cohorts (https://initialise-project.eu/) to understand how these molecules can modulate priming of the immune system in early life. We will synthesize the conjugates of interest and perform immunometabolic and primary human T-cell function assays to identify the mechanism underlying their immunomodulatory role.
INITALISE has a wide range of samples available as well as a wealth of metadata thus making the ideal cohort to study these novel conjugations. The plan is to acquire targeted immune related proteomics and metabolomics from 4624 serum samples as well as metabolomics from 1403 stool samples. This project will add on the novel conjugates to the existing data series, further enriching the information obtained from these valuable cohorts.

References
1. Gentry EC, et al. Nature. 2024;626(7998):419-426.
2. Hyotylainen T, et al. Lancet Planet Health. 2024;8(1):e5-e17.

Key words: Host response; Immune modulation; Novel bile acid conjugates; Metabolomics; Immunometabolism,
Diagnostics.

Main supervisor: Vilhelmiina Parikka, Turku University Hospital, Department of Pediatrics and Adolescent Medicine; University of Turku, MediCity Research Laboratories, InFLAMES Research Flagship Center and Preclinical Imaging Laboratory at Turku PET Centre, vilpar@utu.fi

Other supervisor(s): Otto Kauko, Turku Bioscience Centre, University of Turku, otkauko@utu.fi

Doctoral researcher: Katri Korpela

Pilot project description

Neonatal hypoxic-ischemic encephalopathy is the most severe birth complication and one of the leading causes of death or severe morbidity in newborns, caused by inadequate blood flow and oxygen delivery to the brain during or shortly after birth.

This project aims to provide novel insights into the role of inflammation and to identify novel biomarkers to predict brain injury in the early phase. The project will be carried out at the Neonatal Intensive Care Unit of Turku University Hospital and the MediCity Research Laboratories of the University of Turku.

The project will use samples from our prospective case-control follow-up study at Turku University Hospital. A comprehensive analysis of proteins from patients’ blood samples will be performed to determine how the inflammatory process proceeds during the first hours and days after injury. We plan to perform: 1) targeted analysis of inflammatory and endothelial injury-associated cytokines and other proteins together with markers of neuronal injury using Olink’s proximity extension assay and a novel single molecular array technique (Simoa®) and 2) proteomics and metabolomics analyses of the clinical samples using mass spectrometry at the Turku Proteomics Facility and Turku Metabolomics Centre to facilitate the identification of proteins and changes in the serum metabolome associated with hypoxic-ischemic encephalopathy.

The results of the multiomics analyses will be evaluated as part of the patient’s clinical situation and compared with the level of neurological injury. This project aims to provide the basis for biomarker development, in particular point-of-care testing, to facilitate early identification of the most severely affected individuals who may benefit from therapeutic interventions.

Key word(s):Neonatal, hypoxia, biomarker, neuroinflammation, brain injury, clinical study

Main supervisor: Professor Olli Pentikäinen, InFLAMES PI, Institute of Biomedicine, University of Turku,
olli.pentikainen@utu.fi, https://www.medchem.fi

Other supervisor(s): PhD, Chief Scientific Officer Sanna Niinivehmas, Aurlide Ltd.
Sanna.niinivehmas@aurlide.fi https://www.aurlide.fi
PhD, Docent Pekka Postila, University of Turku (InFLAMES) and Aurlide Ltd.
Pekka.postila@utu.fi https://www.medchem.fi

Doctoral researcher: Paola Moyano Gómez

Pilot project description

Immunological disease target proteins often lack binding sites for small-molecule drugs,
hindering their usage in drug discovery. Monoclonal antibodies, though effective, are
expensive and not orally available. Macrocycles offer a promising solution, combining the advantages of antibodies and small molecules, presenting a cost-effective and orally administered alternative.
This project uses our pioneering computational macrocycle discovery platform to yield (pre-)clinical candidates for immunological conditions like ulcerative colitis, rheumatoid arthritis, and psoriasis. This is obtained by targeting TNF-alpha, interleukin-23, and different integrins, all lacking small-molecule drugs. All designed molecules are synthesized and extensively tested with various in vitro techniques, including recombinant protein and cellular assays. Macrocycles offer, in general and especially with our enhancements, several significant advantages over antibody drugs:
1. Potency and Specificity: We can rationally design macrocycles that modulate target proteins potently and specifically, thus inhibiting wished signaling pathways with minimized offtarget effects.
2. Enhanced Pharmacokinetics: Our macrocycles are designed for optimal properties, including stability against degradation, oral bioavailability, water solubility, permeability, and metabolic stability, improving drug delivery and distribution.
3. Reduced Immunogenicity: Compared to antibodies, macrocycles exhibit lower
immunogenicity, decreasing the risk of developing anti-drug antibodies and ensuring
sustained treatment efficacy and safety.
Candidates’ success in this project requires molecular modeling and medicinal chemistry expertise. Effective collaboration and communication are essential for translating innovative therapies from concept to reality with research group members and collaborators in academia and industry. The project is performed at MedChem.fi -laboratory, Institute of Biomedicine.

Key words: Macrocycle, Tumor necrosis factor-alpha, Interleukin-23, Drug discovery, Molecular modeling

Main supervisor: Professor Olli Pentikäinen, InFLAMES PI, Institute of Biomedicine, University of Turku
olli.pentikainen@utu.fi, https://www.medchem.fi

Other supervisor(s): PhD, Chief Scientific Officer Sanna Niinivehmas, Aurlide Ltd., Turku
Sanna.niinivehmas@aurlide.fi, https://www.aurlide.fi
Adj. Professor Carlos Rogerio Figueiredo, Institute of Biomedicine, University of Turku rogerio.defigueiredo@utu.fi, https://www.miorg.fi

Doctoral researcher: Kseniia Petrova-Szczasiuk

Pilot project description

This PhD project seeks to design and identify novel macrocycles that target important proteins in key immune signaling pathways to develop potential therapeutic agents for autoimmune diseases and cancer. This project will combine novel computational methods to rationally design macrocycles to modulate the protein-protein interactions, synthesize those molecules, and use experimental methods to verify the biological functionality and guide the development. Monoclonal antibodies (mAbs) have revolutionized drug discovery, providing highly specific and compelling therapeutics for various diseases. However, there is an exciting opportunity to use complementary modalities with improvements. In this context, macrocycles present a unique class of compounds that can bridge the gap between small molecules and biologics. With their ability to modulate challenging targets, such as protein-protein interactions, macrocycles can build upon the success of mAbs and address limitations like oral bioavailability and intracellular target engagement. Thus, macrocycles can continue the success initiated by mAbs, offering new possibilities for target engagement and drug design.

The project is based/supervised at the MedChem.fi laboratory (Prof. Pentikäinen) and Aurlide Ltd. (Dr. Niinivehmas), who jointly develop the macrocycle technology. Furthermore, the supporting in vitro measurement and comparison to mAbs technology are performed at the laboratory of supporting supervisor Dr. Figueiredo. Also, other projects in similar settings will be accomplished. Our setting provides the potential for developing novel drug candidates, where collaboration and communication allow the translation of innovative therapies from concept to reality with research group members and collaborators in academia and industry.

Key words: Macrocyclic inhibitors, Computer-aided drug discovery (CADD), drug design, inflammation, cancer

Main supervisor: Docent Pia Rantakari, InFLAMES Research Flagship Center; Turku Bioscience Centre; Infection and Immunity Research Unit, Institute of Biomedicine, University of Turku, and Åbo Academi University pia.rantakari@utu.fi plvap.utu.fi

Other supervisor(s): PhD Damien Kaukonen, InFLAMES Research Flagship Center, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
damien.kaukonen@utu.fi
Docent Tapio Lönnberg, InFLAMES Research Flagship Center, Turku Bioscience Centre, taplon@utu.fi

Group website: https://plvap.utu.fi/

Doctoral researcher: Nicholas Booth

Pilot project description

Macrophages are the first immune cells to emerge in the developing embryo, playing a critical role in organ development, homeostasis, immunity, and repair. However, their involvement in various human diseases underscores their complex role. The remarkable adaptability of macrophages is largely attributed due to their plasticity, allowing them to respond to tissue-specific signals while retaining their core function as tissue phagocytes.
Most tissue-resident macrophages arise from monocytes, which are derived either from the fetal liver monocytes during embryonic development or from bone marrow-derived monocytes later in life. Embryonic monocyte-derived tissue-resident macrophages occupy the tissue’s niches earlier in life and contribute significantly to the modification of the tissue environment. A key unresolved question is whether the functional diversity seen in macrophage populations is driven by essential differences in the monocytes from which they originate or if it is the timing and environment of monocyte recruitment and differentiation that shape the macrophage phenotype as bone marrow-derived monocytes mature into macrophages in a very different tissue context than their embryonic counterparts.
The proposed research project aims to deepen our understanding of macrophage diversity and plasticity, which are critical for immunity. Understanding how different tissue environments and developmental origins influence macrophage behavior will shed light on new therapeutic strategies for manipulating macrophage function in a variety of diseases, including infections, cancer, and autoimmune conditions. This knowledge could pave the way for novel immunotherapies targeting macrophage plasticity to enhance or dampen specific immune responses for optimal disease outcomes.
To achieve its goals, the project will combine computational biology, including artificial Intelligence-driven machine learning, bioinformatics, and in vivo experimentation.

Key words: Macrophages, monocytes, ontogeny, single-cell transcriptomic analysis

Main supervisor: Docent Pia Rantakari, InFLAMES Research Flagship Center; Turku Bioscience Centre; Infection and Immunity Research Unit, Institute of Biomedicine, University of Turku, and Åbo Academi University pia.rantakari@utu.fi plvap.utu.fi

Other supervisor: PhD Heli Jokela, InFLAMES Research Flagship Center, Turku Bioscience Centre, Infection and Immunity Research Unit, Insitute of Biomedicine, University of Turku and Åbo Academi University, heli.jokela@utu.fi

Group website: https://plvap.utu.fi/

Doctoral researcher: Janni Ollikainen

Pilot project description

Over the past decades, the global prevalence of obesity and its associated health complications, including diabetes and cardiometabolic diseases, has surged. Brown adipose tissue (BAT) is a specialized fat that consumes excess energy under sympathetic nervous system activation. It can regulate glucose and lipid metabolism, making it a promising drug development target for obesity and metabolic disorders. Notably, active BAT is present in healthy adults, children, and adolescents but not in obese adults. Childhood obesityinduced inflammation predisposes to metabolic syndrome and type 2 diabetes in adulthood. Thus, it is vital to identify early regulatory factors of BAT development and activation to combat obesity and obesityrelated systemic inflammation. All adult tissues have a combination of resident macrophages of fetal and adult-derived origins. These tissuespecific macrophages are involved in tissue development and balanced function, but some may also contribute to inflammation and disease formation. The proposed BATMAC project aims to unravel the intricate relationship between fetal macrophages and BAT development.
To date, the BATMAC project’s data in mice reveals early macrophage involvement already at embryonic day (E)15.5. These macrophages exhibit distinct phenotypic profiles from E17.5 onward. Most macrophages in developing BAT originate from the fetal liver and interact closely with developing sympathetic nerves. However, the fetal liver-derived macrophages serve a transient role, essential for tissue development. Postnatally, they are entirely replaced by adult-derived macrophages. Deficiency of fetal macrophages results in disrupted BAT morphogenesis and thermogenesis in newborns. While these findings shed light on the early stages of BAT development, further research is needed to elucidate the precise mechanisms underlying macrophage-BAT interactions and understand how developmental programming influences core macrophage functions in BAT.

Key words: fetal macrophages, brown adipose tissue, tissue development, obesity,
developmental programming

Main supervisor: Professor Anne Roivainen, Turku PET Centre, anne.roivainen@utu.fi,
https://inflammation-imaging.utu.fi/

Other supervisor: Academy Research Fellow, Adj. Prof. Ilkka Heinonen, Turku PET Centre,
ilkka.heinonen@utu.fi

Doctoral researcher: Shiva Latifi

Pilot project description

Physical activity and exercise are well-known to prevent many diseases, including different cancers. Physical activity is also important in the treatment of cancer treatment, as it has been shown that exercise after diagnosis is associated with improved quality of life, reduced fatigue, complications, cancer recurrence, and ultimately mortality. Pre-clinical studies suggest that the majority of exercise-mediated improvements in tumor size reduction are mediated by the immune system, particularly by natural killer cells and cytotoxic Tcells, but this topic has rarely been investigated in real patients and better mechanistic insights are urgently
needed. However, we have recently elucidated that especially natural killer cells and cytotoxic CD8+ T-cells increase as a result of acute exercise in the blood circulation of lymphoma and breast cancer patients. Therefore, in this study we will address and ask for the first time using whole body PET imaging whether these immune cells go to the tumor after exercise, or if they do not, where they go in these cancer patients?
We hypothesize that PET imaging with 89Zr-anti-CD8 minibody and unique vascular adhesion protein-1 (VAP- 1)-targeted 68Ga-DOTA-Siglec-9 tracer developed at the University of Turku/Turku PET Centre show that cytotoxic T-cells enter the tumor, and that the accumulation of 68Ga-DOTA-Siglec-9 in the tumor increases
after exercise as an indicator of leukocyte extravasation. Other immunological aspect will also be investigated by the state-of-the-art methods at single-cell and omics core facilities of the University of Turku.

Key words: immunology, positron emission tomography, immunological molecular imaging, exercise, cancer, patients

Main supervisor: Professor Anne Roivainen, Turku PET Centre, anne.roivainen@utu.fi,
https://inflammation-imaging.utu.fi/

Other supervisor: Ass. Professor Diana Toivola, Åbo Akademi University diana.toivola@abo.fi,
MD, PhD Jukka Koffert, jukka.koffert@utu.fi,

Doctoral researcher: Mitra Gerami

Pilot project description

Although glucose analog, 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) enables imaging of metabolically active cells, it cannot distinguish metabolic uptake between immune cells and other cells. FDG is non-specific method for detecting immune activation in several inflammatory diseases, but has limited value in imaging inflammatory bowel disease (IBD). Positron emission tomography/computed tomography (PET/CT) imaging using radiolabelled ligands of folate receptor-􀉴 (FR-􀉴, expressed on activated macrophages) and fibroblast activation protein (FAP, expressed on active myofibroblasts and fibroblasts) are promising approaches to study inflammation and fibrotic activity, but their value in IBD has not yet been studied. We have demonstrated earlier that FR-􀉴-targeted PET identifies activated macrophages associated with experimental models of neuroinflammation and cardiovascular diseases. We hypothesize that molecular imaging of FR-􀉴 and FAP expression can provide information on the dynamics of intestinal inflammation and fibrosis, and provide a quantitative assessment of treatment efficacy. FR-􀉴 and FAP-targeted PET imaging will be evaluated in established experimental models of IBD, already setup in our laboratories in Turku. Feasibility of novel in vivo PET/CT imaging approaches will be studied at different phases of disease using dedicated small animal device, combined with histological and quantitative immunostaining analysis of intestinal immune cells and measurement of IBD disease activity index. In addition, a combination of longitudinal FR-􀉴 and FAP-targeted imaging will be evaluated to investigate the relationships between inflammation and fibrosis, and treatment-induced intestinal immune responses. Other immunological aspect will also be investigated by the state-of-the-art methods at single-cell and omics core facilities of the University of Turku. The ultimate goal is to investigate the utility of FR-􀉴 and FAP-targeted imaging in a small cohort of patients
with IBD.

Key words: fibrosis, inflammation, inflammatory bowel disease, immunological molecular imaging,
Crohn’s disease, colitis ulcerosa

Main supervisor:  Assoc Prof Pekka Ruusuvuori, Institute of Biomedicine, University of Turku, pekka.ruusuvuori@utu.fi

Research group website: https://ruusuvuorilab.utu.fi

Other supervisor(s):

Research director Leena Latonen, Institute of Biomedicine, University of Eastern Finland, leena.latonen@uef.fi

Prof Pekka Taimen, Institute of Biomedicine, University of Turku & Turku University Hospital, pepeta@utu.fi

Doctoral researcher: Niloufar Rahimizadeh Asli

Pilot project description

Spatial multiomics measurements are increasingly common in modern biomedical research where diseases (such as cancer) and human health (such as immune system) are studied. Connecting the spatial measurements to the essential histological phenotype and morphology allows to extract a highly informative “pathomics” characterization of the sample, where individual cells in the tissue are combined with the proteomics profile in the corresponding location. Here, we develop the computational methods for such analysis.

This project focuses on automated analysis and interpretation of histology images as well as associated spatial proteomics measurements with the help of deep learning based artificial intelligence (AI). Specifically, we will focus on tissue type detection from histology, integrated analysis of immunohistochemical stainings to quantify the locations and spatial relations of tumor cells and tumor associated immune cells. Finally, we will enable combination of histology level representation to spatial proteomics profiles of the tissue using state-of-the-art computational methods such as graph neural networks. This AI-driven spatial profiling will enable generating highly detailed multiomic profiling of tumor and immune cells within their spatial context in tissue. The topic has a high potential for publications both from method development and immunology-related application angle.

The work requires skills in machine learning and image analysis using relevant programming environments. The work will be carried out at the Institute of Biomedicine/UTU, and visits to co-supervisors’ host institutes as well as to companies involved in the steering committee are encouraged. We expect the project to be highly useful for the immunology and cancer research communities, and it has the potential to also advance disease diagnostics. The project has a high level of synergy with several immunology-driven research topics within and beyond the ImmuDocs pilot program.

Key words: artificial intelligence; computational immunology; pathomics; spatial proteomics; cancer; diagnostics

Main supervisor:  Assoc Prof Pekka Ruusuvuori, Institute of Biomedicine, University of Turku, pekka.ruusuvuori@utu.fi
Website: https://ruusuvuorilab.utu.fi/

Other supervisor(s):

Research director Leena Latonen, Institute of Biomedicine, University of Eastern Finland, leena.latonen@uef.fi

Prof Pekka Taimen, Institute of Biomedicine, University of Turku & Turku University Hospital, InFLAMES Research Flagship, pepeta@utu.fi

Doctoral researcher: Muhammad Adnan Khan

Pilot project description

Immunological landscape of human tissue is typically determined through applying specific histochemical stainings to 2D tissue sections revealing quantity and location of immunologically active cell types. Such measurements can reveal similarities and differences between tissue microenvironments in normal and tumor tissue. Quantification of the tissue microenvironment computationally from immunostained tissue and other spatial measurements is possible using modern tools based on artificial intelligence (AI). Spatial environment within tissue is not, however, two-dimensional – but taking into account the true 3D spatial environment of the tissue sets a significantly more challenging task for the computational tools, which are currently lacking. Here, we set out to develop computational methods for 3D modeling of the immune component in normal and cancerous tissue and to study the immune landscape of tissue quantitatively and through visual exploration using virtual reality (VR).

Specifically, we will model the 3D tissue environment by applying already existing, in-house developed reconstruction pipeline using murine spleen and prostate as the model, develop artificial intelligence based computational methods for quantitative characterization of immunological cells, and visualize the immune component by applying a dedicated VR application already developed in the hosting research group. The work requires interest towards immunology and histology, and skills in machine learning and image analysis using relevant programming environments. The research will be done at the Institute of Biomedicine/UTU secondments to collaborating companies are encouraged. We expect the project to be highly useful for the immunology and cancer research communities, and it has the potential to also advance disease diagnostics. This project has a high level of synergy with several immunology-driven research topics within and beyond the ImmuDocs pilot program. After graduation, the candidate will have highly relevant data science skills for industrial positions.

Keywords: Immunology, immunohistochemistry, 3D histology, artificial intelligence, virtual reality

Main supervisor: Professor Marko Salmi, MediCity, University of Turku; marko.salmi@utu.fi; https://sites.utu.fi/salmilab/

Other supervisor(s): PhD Ruth Fair-Mäkelä, Institute of Biomedicine rufair@utu.fi

Doctoral researcher: Pia Sundqvist

Pilot project description

Fibroblastic reticular cells (FRC) encompass a multitude of cell types found in primary and secondary lymphoid organs. They play key roles in immune reactions e.g. by producing chemotactic cues and growth factors for leukocytes, by forming the reticular conduits for antigen transport and by generating the extracellular matrix. Our preliminary data show that FRCs unexpectedly express the filter-forming protein PLVAP (previously thought to be strictly endothelial cell specific), and that absence of PLVAP severely compromises FRC function. Interestingly, FRC-like cells are also known to exist in ectopic lymphoid tissues (tertiary lymphoid organs) in patients with chronic inflammatory conditions.
The aims of the project are 1) to study novel functions of PLVAP in FRCs and 2) to compare the human FRC phenotypes and functions in secondary and tertiary lymphoid organs.
In subproject 1, the expression and regulation of PLVAP in FRCs will be analyzed using bioimaging and electron microscopy. FRC-specific conditional Plvap knock-outs will be used for studying the cytokine secretion, leukocyte traffic, conduit function and matrix composition in lymph nodes under normal and inflammatory conditions. In subproject 2, characteristics of human FRCs in lymph nodes and tertiary lymphoid organs will be compared using single-cell transcriptomics. Furthermore, human FRCs will be isolated for mechanistic in vitro analyses (cytokine secretion, lymphocyte binding, matrix production etc).
The results will provide novel insights into the mechanisms of FRCs function in lymphoid tissues. In addition, the human studies have translational potential for discovering targets to modulate FRC function for desired anti-inflammatory effects. The study will be carried out in MediCity as a part of the InFLAMES Flagship.

Key words: Lymphoid tissues, Fibroblastic reticular cells, Inflammation, Leukocyte trafficking, Antigen transport

Main supervisor: Professor Marko Salmi, MediCity, University of Turku; marko.salmi@utu.fi; https://sites.utu.fi/salmilab/

Other supervisor(s): PhD Ruth Fair-Mäkelä, Institute of Biomedicine, rufair@utu.fi

Doctoral researcher: Pinja Thorén

Pilot project description

Lymph nodes are needed for the generation of adaptive immune responses against foreign antigens. When the antigens breach body surfaces at the periphery (e.g. through the skin), they are carried by the lymphatic vessels to the draining lymph node. There they enter into the subcapsular sinus and further drain to medullary sinuses. These sinuses are lined by lymph node specific lymphatic endothelial cells (LECs), which regulate the entry of lymph-borne antigens and cells into the lymph node parenchyma.
In this project we hypothesize that lymph node LEC respond to vaccine antigens by major structural and functional adaptations. We expect that these LEC alterations contribute to the generation of a favorable niche for triggering protective immune reactions. Our objectives are to 1) dissect early LEC responses to different vaccinations at molecular level and 2) understand the structural organization of the LEC barrier in the complex sinus systems.
We will use experimental immunization models with clinically relevant vaccines, including mRNA vaccines and analyze transcriptomic changes in isolated LECs by scRNA-seq and proteomic methods. We will study the structural alterations with super-resolution microscopy. Based on the observed changes, we will use functional in vivo assays to measure changes in LEC-dependent antigen handling and leukocyte traffic. The study will be carried out in MediCity as a part of the InFLAMES Flagship
The results will provide novel insights into the effects vaccinations have on LECs in the draining lymph node and their functional consequences in mounting protective immune responses. The results will also dissect the architecture of the complex sinus systems at an unprecedented level.

Key words: Lymph nodes, lymphatic endothelial cells, vaccinations, scRNA-seq, immune responses

Main supervisor: Professor Antti Saraste, Turku PET Centre, antti.saraste@utu.fi, https://inflammation-imaging.utu.fi/

Other supervisor(s): Professor Anne Roivainen, Turku PET Centre, anne.roivainen@utu.fi, https://inflammation-imaging.utu.fi

Doctoral researcher: Arman Anand

Pilot project description

Fibrosis is a common mechanism underlying cardiac dysfunction in various cardiac diseases. Positron emission tomography/computed tomography (PET/CT) imaging using radiolabeled ligands of fibroblast activation protein (FAP) expressed on active myofibroblasts and fibroblasts is a promising approach to study fibrotic activity, but it’s value in cardiac diseases remains to be studied. We have demonstrated earlier that targeted PET of folate receptor-β (FR-β) identifies activated macrophages in acute and chronic cardiovascular diseases. We hypothesize that molecular imaging of FAP and FR-β can provide information on dynamics of myocardial fibrosis and inflammation before development of irreversible myocardial injury and dysfunction.
We will evaluate novel FAP targeted PET tracers in established experimental models of myocardial infarction, pressure overload and autoimmune myocarditis. Feasibility of in vivo imaging will be studied at different phases of diseases using small animal PET/CT scanner combined with histological validation and measurement of cardiac function. Furthermore, combination of FAP and FR-β targeted imaging will be evaluated to study relationships between fibrosis and inflammation.
This projects aims at developing new molecular imaging approaches of myocardial fibroblast activation and inflammation after myocardial infarction, pressure overload and autoimmune myocarditis. This could be useful for the evaluation of targeted cardioprotective therapies and diagnostic assessment of cardiac diseases.

Key words: Fibrosis, Inflammation, Positron emission tomography, Molecular imaging, Myocardial infarction, Heart failure

Main supervisor: Tero Soukka, PhD, Professor, Biotechnology, Department of Life Technologies, University of Turku
https://fi.linkedin.com/in/tero-soukka-4835bb2
https://research.utu.fi/converis/portal/detail/Person/794864

Other supervisor(s):
Alice Ylikoski, PhD, Senior Manager, Assay Technology, Radiometer Turku Oy;
Adjunct Professor (Docent), Nucleic Acid Analytics; Tampere University
alice.ylikoski@radiometer.fi
https://fi.linkedin.com/in/alice-ylikoski-34679530
Satu Lahtinen, DSc (Tech), University Lecturer, Biotechnology, Department of Life Technologies, University of Turku
https://fi.linkedin.com/in/satu-lahtinen-137196134

Doctoral researcher: Roope Korkea-aho

Pilot project description

Technologies enabling higher binding capacity and antibody reactivity on solid-phase surfaces are needed to develop more rapid and sensitive immunoassays applicable in point-of-care testing and acute care immunodiagnostics for detection of biomarkers in different disease conditions, such as cardiac complications, infection and sepsis.

The objective of the proposed pilot project is to study construction of three-dimensional streptavidin base layer as generic solution for high capacity immobilisation of biotinylated antibodies on polystyrene microwells. The hypothesis is that using streptavidin conjugates of flexible polymers, adsorbed either directly on the polystyrene surface, or through strongly adsorbed anchor proteins, not only high biotin binding capacity, but also high reactivity of immobilized biotinylated antibodies can be achieved. The high surface density of antibodies and their flexible coupling in the three-dimensional layer should result in accelerated binding kinetics when the diffusion limitations are removed. The rapid binding kinetics further facilitates improved sensitivity when the non-specific binding on the surface is under control.

The project plan of the study has two main subobjectives: 1) Construction of streptavidin polymer conjugates, their immobilization on microwells both directly and via anchor protein to form three-dimensional streptavidin surfaces, and characterization of the biotin and biotinylated antibody binding capacity and stability of the produced surfaces. 2) Evaluation of the immunoassay performance, including assay kinetics, sensitivity and dynamic range with a model biomarker, using the most promising candidates of the produced surfaces as base layers for immobilization of the biotinylated antibodies.

This study is carried out at Biotechnology unit in intended collaboration (e.g., co-supervision, reagent support, visit to company) with Radiometer Turku Oy, which develops and manufactures immunoassays for acute care diagnostics.

Key words: Immunodiagnostics, point–of–care testing, streptavidin, antibody immobilization, protein adsorption

Main supervisor: Tero Soukka, PhD, Professor, Biotechnology, Department of Life Technologies, University of Turku
https://fi.linkedin.com/in/tero-soukka-4835bb2
https://research.utu.fi/converis/portal/detail/Person/794864
Other supervisor(s):Satu Lahtinen, DSc (Tech), University Lecturer, Biotechnology, Department of Life Technologies, University of Turku
https://fi.linkedin.com/in/satu-lahtinen-137196134
PhD Kirsti Raiko, University of Turku, Department of Life Technologies, kisrai@utu.fi

Doctoral researcher: Risto Jokinen

Pilot project description

Alzheimer’s disease (AD) is an inflammatory autoimmune disease and a growing burden to the individual and society. There are several biomarkers under investigation as potential early diagnostic markers for AD, like plasma amyloid-beta 42/40 (Aβ42/Aβ40), plasma phosphorylated-tau 217 (p-tau 217), apolipoprotein E, ptau 181, and neurofilament light polypeptide (NfL). Currently, most of the assays for them are based on risky sample matrix (cerebrospinal fluid), having higher concentrations of the markers. Alternatively, cumbersome detection technologies, like SIMOA or mass spectrometry, are required to chase the low analyte concentrations from plasma samples. Professor Tero Soukka’s group has shown that detection technology based on upconverting nanoparticles (UCNP) in a standard 96-well plate assay can gain similar sensitivity compared to more complex SIMOA technology (Raiko et al. Clin. Chim. Acta 2021). UCNPs are inorganic luminescent nanoparticles that emit visible light upon excitation under near-infrared radiation. This upconversion process is rare and, therefore, autofluorescence from surrounding materials can be spectrally omitted from the emission enabling extraordinary sensitivity.
This project aims to develop a 96-well plate based immunodiagnostic assay for AD. It would result in an accessible, cost-efficient and simple tool for AD diagnostics from a standard blood sample without compromising the performance when ultra-sensitive UCNP technology is utilized. The functionality of the assay would be compared to current state-of-the-art technology and a clinical sample pool will be used to prove the performance of the assay. The work will be conducted at the UTU, Department of Life Technologies and Uniogen under supervision of Prof. Soukka, who’s an expert in immunoassay development and UCNP technology. In addition to the simplified diagnostics, the assay improves patient stratification for clinical trials having a great value for pharmaceutical industry.

Key words: Alzheimer’s disease diagnostics, Upconverting nanoparticles, ultra-sensitive immunoassays, autoimmune disease, inflammatory disease, immunoassay development

Main supervisor: Professor Cecilia Soderberg-Naucler, Institute of Biomedicine, University of Turku, InFLAMES Research Flagship, cecilia.naucler@utu.fi

Other supervisor(s): Professor Jiri Bartek, Karolinska Institutet, jb@CANCER.DK

Associate Professor Dhifaf Sarhan, Karolinska Institutet,dhifaf.sarhan@ki.se 

Doctoral researcher: Maedeh Alipour

Pilot project description

Glioblastoma (GB) is an incurable tumor with a very dismal prognosis. Emerging evidence demonstrate that GB tumors are infected with cytomegalovirus (CMV) and that anti-viral therapy or vaccination against this virus may highly improve survival time for patients. We found that anti-viral therapy prevents radiation induced CMV reactivation that occurs in almost 50% of patients, of which a majority develop rapid tumor recurrence.
We hypothesize that immune control of CMV is important to prevent clinical CMV reactivation in GB patients. We found that about 50% of the population who carry HLAE-0101 alleles can activate memory NK cells to control CMV infections. NK cells and gd T cells appear to be better than conventional T cells to infiltrate tumors as they are insensitive to suppressive effects of myeloid suppressor cells and regulatory T cells. Thus, patients who reactivate clinical CMV infections and develop rapid tumor recurrencies may be unable to mount proper NK cell and gd T cell responses.
To clarify this, we have collected blood and tumor samples from patients enrolled in VIGAS2 a randomized controlled study that aims to clarify if anti-CMV therapy can improve the prognosis for GB patients. Currently 180 of 220 patients have been enrolled. Tumor tissue specimens will be subjected to comprehensive immune cell phenotyping, CMV proteins, characterization of the DNA damage responses and epigenetic profiles in samples from patients who reactivate or do not reactivate CMV following radiation therapy. CMV peptides will be used to activate conventional T cells, NK cells and gd T cells in PBMCs that have been collected at different time points to determine the fitness of the anti-CMV immune response. Seahorse analyses will determine metabolic profiles of active cells. IgG and IgM levels in plasma samples will be determined by ELISA to assess for CMV reactivation. PCR will assess for virus levels in blood. Data will be correlated to clinical parameters and outcome.

Key words: glioblastoma, cytomegalovirus, NK cells, T cells, epigenetics, DNA damage

Main supervisor: Professor Cecilia Soderberg-Naucler, Institute of Biomedicine, University of Turku, InFLAMES Research Flagship, cecilia.naucler@utu.fi

Other supervisor(s): Assistant Professor Xiang-Guo Li, Turku PET Centre, li.xiang-guo@tyks.fi
Associate Professor Dhifaf Sarhan, Karolinska Institutet, dhifaf.sarhan@ki.se

Doctoral researcher: Sofia Valkonen

Pilot project description

A number of different tumors have today been shown to be positive for cytomegalovirus (CMV) proteins; for example, more than 90% of brain tumors, neuroblastoma, sarcomas, breast, colon, prostate and ovarian cancer are CMV positive. Both primary tumors as well as >95% of lymphode and distant metastases from breast and colon cancer are virus positive, while non-tumor cells in healthy tissues surrounding the primary tumors or their metastases are virus negative. Thus, CMV positivity is confined to tumor cells and may therefore provide a novel therapy target in cancer treatment.

As a proof of concept model, we and others have shown that anti-viral therapy or vaccination against CMV in patients with glioblastoma highly improve expected survival time. We found that anti-viral therapy prevents radiation induced CMV reactivation that occurs in almost 50% of these patients, of which a majority
develop rapid tumor recurrence within 3 months. This is fully preventable with anti-viral therapy and show promise to enhance survival time from 13.5 to 29.7 months.

We hypothesize that a combined therapy with anti-viral drugs and an immune based targeted approach towards CMV infected cells in the tumor, will further increase the efficacy of anti-CMV therapy in CMV positive cancer patients and improve treatment outcome. This project intends to compare the efficacy of three immune based therapies; a peptide T cell vaccine, a CMV targeted antibody therapy (conjugated with a toxin) and an adoptive NKG2C therapy, with or without combination with anti-CMV therapy in glioblastoma and breast cancer mouse models. The PhD candidate will study both human xenograft tumors and MCMV indcuced metastatic disease to determine the most effective immune-based anti-CMV approach for advancement to a clincial phase I trial. The research is conducted at Medicity, University of Turku.

Key words: Glioblastoma, breast cancer, cytomegalovirus, peptide vaccine, NK cells, T cells

Main supervisor: Pekka Taimen, Professor of Molecular Pathology, Institute of Biomedicine, University of Turku, pepeta@utu.fi

Research group website: www.taimenlab.fi

Other supervisor(s):

Rogerio De Figueiredo, Adjunct Professor, Institute of Biomedicine, rogerio.defigueiredo@utu.fi, https://miorg.fi/

Pekka Ruusuvuori, Associate Professor, Institute of Biomedicine, pekka.ruusuvuori@utu.fi, https://ruusuvuorilab.utu.fi/

Doctoral researcher: Sofia Erkkilä

Pilot project description

Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 inhibitors, have revolutionized the treatment of many solid cancers by leveraging the body’s immune system to target and eliminate malignant cells. ICIs have also been approved for the treatment of advanced and metastatic bladder cancer (BC), which typically has a poor prognosis. In diagnostic pathology, immunohistochemistry is used to determine the expression of PD-L1 in tumor cells and tumor-associated immune cells. PD-L1 positivity predicts a favorable treatment response for ICIs in some patients, but not all. The mechanistic background for such differences is unclear and presumably multifactorial, related to intratumoral heterogeneity and other modulators of anti-tumor immune response.

This project, carried out at the Institute of Biomedicine, University of Turku, is focusing on detailed cellular phenotypes and genotypes related to PD-L1 expression in BC. Already available and newly established patient-derived tumor cell cultures will be used to develop an in vitro assay, where the potency of patients’ own peripheral blood immune cells to attack tumor cells is tested. The degree of cell death in the presence or absence of ICIs will be compared to the PD-L1 status of the tumor cells, as well as the parental tumor, and real-life treatment response when available. Single-cell RNA sequencing will be used to determine the most differentially expressed genes between PD-L1 positive and negative tumor cells and to identify potential novel biomarkers associated with PD-L1 status. Meanwhile, tissue microarrays from previously operated patients and a CNN-based approach will be utilized to train an AI algorithm to detect tumor-infiltrating immune cells, tumor cells, and their PD-L1 status from routine HE-stained slides. These studies will provide insights into PD-L1-related anti-tumor immune biology and may offer tools for future diagnostics and patient stratification in BC and potentially also in other solid cancers.

Key words: PD-L1, bladder cancer, immuno-oncology, artificial intelligence, tumor heterogeneity, immunohistochemistry

Main supervisor: Akira Takeda, MediCity Research Laboratory and InFLAMEs fragship, University of Turku, akitak@utu.fi

Research group website: takedalab@utu.fi

Other supervisor(s): Alexander Mildner, MediCity Research Laboratory and InFLAMEs flagship, University of Turku, alexander.mildner@utu.fi, mildnerlab@utu.fi

Doctoral researcher: Dinghao Zheng

Pilot project description

Recent advances in single-cell technologies, such as single-cell RNA-sequencing (scRNA-seq) and both flow and mass cytometry, have provided comprehensive insights into cellular heterogeneity in an unbiased way. These technologies have enabled the identification of novel subsets and markers in both health and disease contexts. Our recent research uncovered heterogeneity among dendritic cells and endothelial cells in human lymph nodes using scRNA-seq, and revealed their distinct functions. However, cellular functions and fate are determined not only by mRNA and protein expression but also by the structural characteristics of the cells themselves. The localization, size, and features of cellular components such as the nucleus, microtubule, mitochondria, endoplasmic reticulum, and cellular membrane are critical to understanding functions of individual cells. In this project, we aim to employ the spectral flow cytometry sorter BD FACSDiscover, which has the capability to capture the images of single cells. This technology will allow us to analyze the expression of cell surface and intracellular markers while simultaneously imaging the cellular structure of the nucleus, microtubules, and mitochondria. Surface and intracellular marker expression in single cells will be analyzed using basic dimensional reduction techniques, while imaging data of the same cells will be processed using deep learning-based image analysis through self-supervised vision transformers. The integration of these datasets may reveal new cellular subsets or state of immune cells. We will apply these approaches to human peripheral blood and lymph node myeloid cells such as dendritic cells, monocytes/macrophages, and neutrophils. This research could significantly deepen our understanding of the underlying mechanisms of immune regulation, potentially leading to breakthroughs in the treatment of immune-related diseases such as autoimmune diseases and cancer.

Key words: myeloid cells, imaging, single-cell analysis, bioinformatics, lymph node, cellular heterogeneity

Main supervisor: Akira Takeda, MediCity Research Laboratory and InFLAMEs fragship, University of Turku, akitak@utu.fi

Research group website: takedalab@utu.fi

Other supervisor(s): Alexander Mildner, MediCity Research Laboratory and InFLAMEs flagship, University of Turku, alexander.mildner@utu.fi, mildnerlab@utu.fi

Doctoral researcher: Nora Alnusairat

Pilot project description

Lymph nodes are central to initiating the immune response. In the context of cancer, cancer cells often metastasize into draining lymph nodes (LNs), from where they can spread to additional organs. The presence of cancer in sentinel LNs is a critical indicator of potential systemic dissemination and a predictor of patient mortality. Within the sentinel LNs, cancer cells grow, colonize, remodel LN architecture, and induce immune tolerance against tumor antigen. Therefore, there is a pressing need to better understand the mechanisms behind LN metastasis and immune evasion in LNs, which are largely uncharacterized in humans. Macrophages, key antigen-presenting cells, can paradoxically suppress immune response under certain conditions. While the role of tumor-associated macrophages (TAM) in primary tumors in dampening tumor immunity is relatively well studied, the subsets and functions of LN macrophages remain largely unexplored. Our preliminary single-cell RNA-seq data uncovered an usual accumulation of macrophage subsets accumulation in metastatic LNs of breast cancer patients compared to paired non-metastatic LNs. Spatial transcriptomic analysis further revealed that specific macrophage subsets encase the colonized metastatic tumor within the LNs. This project aims to isolate distinct macrophage subsets from sentinels LNs using markers identified in single-cell RNA-seq data. We will then examine the role of these subsets, focusing on their capacity to stimulate T cells and induce cancer cell proliferation and metastasis. This research would facilitate our understanding of LN TAM and could help us better understand the underlying mechanism by which metastatic lymph nodes evoke immune suppression.

Key words: macrophage, cancer, lymph node, single-cell RNA-seq, metastasis

Main supervisor: Jorma Toppari, Professor, MD, PhD, Institute of Biomedicine, DIPP research

Other supervisor(s): Mari Vähä–Mäkilä, Institute of Biomedicine, DIPP–research group

Doctoral researcher: Ben Tzu-Pin Tseng

Pilot project description

Join the ImmuDocs project, where we are dedicated to advancing our understanding of Type 1 Diabetes (T1D). In 2021, T1D affected 8.4 million globally, with projections estimating 13.5–17.4 million cases by 2040. Most autoimmune diseases, including T1D, lack a cure due to complexity and incomplete understanding of their underlying mechanisms. Treatments focus on symptom management and immune system activity reduction, highlighting the urgent need for ongoing research and more effective therapies.

Our project in the DIPP research centre aims to investigate the transcriptome and epigenome of peripheral mononuclear blood cells related to T1D, leveraging data collected from the PAMP (Pathogen Associated Molecular Patterns) and DIPP (The Finnish Type 1 Prediction and Prevention) studies. Led by a multidisciplinary team of experts, including immunologists, bioinformaticians, and pediatric endocrinologists, the research seeks to uncover critical insights into the immunoregulation process during the presymptomatic phase of T1D. Using advanced methods, like RNA sequencing and RRBS, we analyze samples collected over the years from children developing T1D. Our unique longitudinal case-control study, coupled with an ex vivo cell model, focuses on screening human innate immune pathways. In this project, you will study a small part of the 17000 samples collected since 2010, including 3700 from children progressing to T1D. The project’s case-control pairs have already been formed, and samples have been selected and sequenced. The ideal candidate for studying epigenome and transcriptome would possess a molecular biology and genetics foundation, bioinformatics skills for data analysis, statistical knowledge for interpretation, critical thinking abilities, and effective communication and collaboration skills. Our goal is to identify targets for new therapies and better ways to diagnose T1D. Join us in our mission to make a difference in the fight against T1D.

Key words: Innate immunity, macrophages, Type 1 diabetes, transcriptome, epigenome

Main supervisor: Saara Wittfooth, University of Turku / Department of Life Technologies / Biotechnology Unit
saara.wittfooth@utu.fi
https://fi.linkedin.com/in/saarawittfooth

Other supervisor(s): Iida Martiskainen, University of Turku / Department of Life Technologies / Biotechnology Unit
iimama@utu.fi
Kirsti Raiko, University of Turku / Department of Life Technologies / Biotechnology Unit
kisrai@utu.fi
https://fi.linkedin.com/in/kirsti-raiko

Doctoral researcher: Helea Junes

Pilot project description

Autoimmune reactions are an important part of immunology. In autoimmunity the immune system recognizes molecules of the body as foreign and initiates an immune reaction that includes production of antibodies against these self-antigens. Such autoantibodies have been widely studied as mediators and diagnostic test target molecules of autoimmune diseases. However, the fact that autoantibodies can also significantly interfere with diagnostic testing of other diseases has received much less attention. For example, it has only recently been discovered that fairly common autoantibodies targeting cardiac troponins (cTn) may falsely elevate the cTn test results by forming large cTn-autoantibody complexes with reduced clearance. As cTn are biomarkers of cardiac tissue injury, cTn tests are used widely for the diagnostics of heart attack and for the assessment of cardiotoxicity of cancer chemotherapy. To date, cTn autoantibodies have been studied only in heart attack patients.
This project aims to investigate cTn autoantibodies in cancer patients on cardiotoxic chemotherapy: the prevalence at different timepoints of treatment, the correlation with measures of cardiotoxicity and the influence on troponin test results in these patients. Understanding the immune response to cardiotoxic agents, particularly the formation and activity of cTn autoantibodies, will improve the monitoring of cardiotoxicity and advance the treatment of cancer patients.
The current methods for detecting cTn autoantibodies are complicated, take several hours and are not suited for clinical routines. Therefore, another important aim of this project is to develop a lateral flow immunoassay for simple and rapid detection of cTn autoantibodies.
The research takes place at the Biotechnology Unit of the Department of Life Technologies, University of Turku and also includes a 2-month visit to Salofa Oy company, which specializes in developing and manufacturing rapid lateral flow tests for diagnostics.

Key words: autoimmunity, autoantibody, cancer, cardiotoxicity, immunoassay, troponin

Main supervisor: Eleanor Coffey

Doctoral researcher: Ali Youssef

Pilot project description

A growing body of evidence underscores the role of immune dysfunction in the early pathogenesis of Parkinson’s disease. Specifically, disturbances in lysosomal degradation and autophagy are observed in immune cells in Parkinson’s disease, particularly associated with gain-of-function mutations in LRRK2 and loss-of-function mutations in GBA, which play a pivotal role in this process. Moreover, dysfunctions in protein degradation via these pathways are believed to be triggered by pathogen infections. Consequently, the accumulation of protein aggregates originating from the gut and systemic immune system eventually infiltrates the brain, leading to the loss of dopaminergic neurons. This project will develop a molecular assay capable of assessing lysosomal dysfunction from immune cell proteomic data for the purpose of patient stratification and monitoring. In addition, the project will analyse data from over 6000 patient samples. Transdiagnostic modular analysis of these cohorts will be applied to identify disease associated networks.

Main supervisor: Guillaume Jacquemet

Doctoral researcher: Marcela Rivera

Pilot project description:

This PhD project aims to unravel the complex interactions between circulating cells (including immune and cancer cells) and endothelial cells, which are crucial for health maintenance and misregulated in various diseases. The candidate will develop and utilize Python-based, open-source imaging tools to establish a comprehensive analysis pipeline, drawing upon lab-developed software like ZeroCostDL4Mic, TrackMate, and CellTracksColab. This will enable the study of cell attachment and transmigration under various conditions, such as inflammation, and employ single-cell image-based profiling to identify endothelial cell traits predictive of circulating cell attachment. This research holds the potential to significantly advance our understanding of cellular mechanisms in cell adhesion and migration, offering insights into novel therapeutic strategies for inflammation and cancer. The project provides extensive training in imaging analysis, machine learning, AI, and drug screening, equipping the candidate for a successful career in the intersecting fields of cell biology, immunology and computational biology. With the support of existing lab resources and expert mentorship, this strategic approach is designed to fulfil the project’s ambitious goals and contribute essential findings to the scientific community.

Main supervisor: Annika Meinander

Other supervisors: Maria Sundvall

Doctoral researcher: Anna Dahlström

Pilot project description

This PhD project focuses on developing ubiquitin-based biomarkers for inflammation and cancer, crucial for early diagnosis and treatment initiation. Chronic inflammation, linked to diseases like inflammatory bowel disease (IBD), heightens the risk of colorectal cancer. Met1Ub chains, associated with NF-κB pathway activation, serve as indicators of inflammation and cancer in cellular and murine models. Aptamers and antibodies facilitate highly sensitive detection methods for Met1Ub chains, applicable in both research and diagnostics. Collaboration with various experts ensures the project’s success, promising significant advancements in understanding and diagnosing inflammation-related conditions and cancers.

Main supervisors: Diana Toivola
and Lauri Polari

Doctoral researcher: Ekta Kotharkar

Pilot project description

Gut diseases and disorders affect the life of over a billion people globally. Their severity varies greatly from minor discomfort to disabling diseases. Inflammatory bowel disease (IBD) is among the most serious ones, but it shares several symptoms with other gut diseases and disorders, which makes the initial diagnosis challenging. This PhD project will focus on a recently identified IBD biomarker, cytoskeletal keratin 7 (K7), that is not expressed in the healthy colon but occurs de-novo in the colonic epithelium of patients with IBD. The project will develop K7-based non-invasive assays to detect IBD and characterize the potential of K7 as an IBD biomarker. The specificity of the K7 expression in IBD compared to other gut diseases will also be established. In addition to diagnostic challenges, the complex molecular factors that contribute to IBD and K7 induction are poorly known. This PhD project also aims to characterize immunological and other molecular mediators affecting K7 regulation in the colon.

Main supervisor: Tiina A. Salminen

Other supervisors: Maija Hollmén

Doctoral researcher: Sondos Abdulmajeed

Pilot project description

Novel cancer treatments complementary to the immune checkpoint targeting therapies are urgently needed to combat currently non-treatable cancers. Macrophage-targeted therapies, which break the immune-tolerance of tumors and assist activating host immune defense mechanisms, belong to these innovative treatments. Targeting Clever-1 with anti-Clever-1 antibody bexamarilimab interferes with the immunosuppressive properties of macrophages and slows the spread of cancer. As part of a larger interdisciplinary effort towards developing Clever-1-targeted immunotherapy, we will determine the 3D structure for Clever-1 and elucidate its interactions with bexmarilimab at the atomic level to uncover inhibitory epitope. The obtained results will enable structure-based drug design of small molecular inhibitors expanding the toolbox for Clever-1-targeted oncotherapy.

Main supervisors: Hongbo Zhang and Silvia Gramolelli

Doctoral researcher: Brandon Gárate

Pilot project description

Current methods for monitoring viral loads rely on PCR-based techniques, which can be time-consuming, labor-intensive, and require specialized personnel and equipment. This project aims to develop PCR-free diagnostic methods for detecting specific viral sequences in patient samples by exploiting the catalytic properties of PNA/MNAzymes nanotechnology. Our technology has already been modified to enable the detection of double-stranded DNA, hence we will use this approach to identify specific DNA sequences for virological and immunotherapeutic applications. By completing this project, the candidate will gain expertise in a range of fields, including nanotechnology, precision medicine, viral infection, and viral technologies.

Main supervisor: Zhi Jane Chen, Faculty of Biochemistry and Molecular Medicine, University of Oulu
zhi.chen@oulu.fi
ttps://www.oulu.fi/en/university/faculties-and-units/faculty-biochemistry-and-molecular-medicine/disease-networks

Doctoral researcher: Sofia Ylinen

Pilot project description

Hypoxia plays a key role in both system and local inflammatory reactions and tumorigenesis. Studies have demonstrated that severity of any inflammatory diseases, including Inflammatory Bower Disease (IBD) depend on hypoxia resistance. It has been previously shown that the HIFs have an important influence in inflammatory bowel disease (IBD) where they are fundamental for epithelial cells to adapt to changes in oxygen tension observed in the gastrointestinal tract.
HIFs are important regulators of T cell response through changes in cell metabolism. The activation, polarization and function of T cells are accompanied by a metabolic switch that is necessary to meet the requirements of each T cell subtype. Further characterization of the role of these proteins in T cell regulation is needed as they are potential therapeutic targets for inflammation.
The goal of this project is to first study how hypoxia affects T helper subset differentiation and function by regulating T cell metabolism. The other aim is to explore the effect of targeting HIF pathway in murine model of intestine inflammation.
The research will be carried out at the Faculty of Biochemistry and Molecular Medicine, University of Oulu.

Key words: T cell, T cell differentiation, hypoxia

Main supervisor: Timo Hautala, MD, PhD, professor in immunology and microbiology
Specialist in internal medicine and infectious disease, Oulu University Hospital and University of Oulu, Oulu, Finland
Research Unit of Internal Medicine and Biomedicine
Email: timo.hautala@oulu.fi
https://www.oulu.fi/en/research-groups/mechanisms-dysfunctional-immunity

Other supervisor(s): Johannes Kettunen, PhD, scientific director of Biocenter Oulu, professor in systems medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
Systems Epidemiology, Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland
Medical Research Center Oulu, Oulu University Hospital, University of Oulu

Doctoral researcher: Katri Ruokamo-Korva

Pilot project description

5.1. Background
5.1.1. Significance of pneumonia
Pneumonia is the leading infectious cause of death with a great societal health burden. The risk of pneumonia is particularly high among the young, immunocompromised patients and elderly males with chronic conditions or those with unhealthy lifestyle issues. However, little is known of genetic factors, both rare and common, that contribute to pneumonia risk.
5.1.2. Host immunity, genetics, and pneumonia susceptibility.
Genetic properties may contribute to infection susceptibility; for example, common variable immunodeficiency (CVID), a condition of defective B cell maturation, is the most common inborn error of immunity (IEI). However, CVID is not a major contributor for pneumonia risk at population level. Therefore, there is a dire need to understand genetic factors that associate with pneumonia risk in large populations.
While IEI conditions are rare, understanding the genetic regulation of immunity at population level can help us to understand mechanisms of pneumonia susceptibility.
5.1.3. CVID; not only defective B cell maturation?
CVID can be caused by at least 20 immunologically active genes among which mutations in NFKB1 are common. NFKB1 is active in Nf-kB pathways with roles not only in B cell development but also in regulation
of inflammation. Preliminary data obtained from FinnGen and Northern Finland Birth Cohorts (NFBC) show that hyperinflammation due to canonical Nf-kB pathway imbalance is significant. While the B cell deficiency can be controlled with IgG replacement therapy, the role of genetically dysregulated inflammation in pneumonia is incompletely understood.
5.1.4. Genome wide associations study (GWAS) supports a role for inflammation in pneumonia.
FinnGen study, Estonian biobank and UK biobank include over 144.000 pneumonia cases; a major finding of our unpublished GWAS data analysis support a role for acute phase inflammation in the need of pneumonia hospitalisation.
Our unpublished data obtained from a cohort of CVID patients, NFBC 1966 population study and FinnGen population study highlights the significance of genetic regulation of inflammation.

Key words: Respiratory infections, pneumonia, genetics, inflammation

Main supervisor: Professor Mika Rämet, Faculty of Medicine and Health Technology, Tampere University
mika.ramet@tuni.fi
https://research.tuni.fi/experimental-immunology
mikaramet.fi

Other supervisor: Ph.D. Sanna Harjula
Sanna.harjula@tuni.fi
https://research.tuni.fi/experimental-immunology

Doctoral researcher: Maiju Junno

Pilot project description
Tuberculosis remains one of the major global health challenges. Today, there are more humans infected with Mycobacterium tuberculosis on the planet than ever before. Currently, there are no effective vaccines to prevent infection with the causative agent Mycobacterium tuberculosis. Tuberculosis research has been hampered by lack of suitable animal models as Mycobacterium tuberculosis is a natural pathogen only for primates. We have developed a zebrafish model of tuberculosis which we use to identify host factors required for normal resistance against Mycobacterial infection. In contrast to many other animal models (mouse, for example), an intraperitoneal infection with a low dose (35 bacteria) of Mycobacterium marinum leads to a latent disease in most individuals in adult zebrafish. Latent infection is characterized by limited mortality, static bacterial counts and constant numbers of highly organized granulomas in few target organs. In this current project, we will use our existing in-house made mutant and transgenic zebrafish lines combined wiith holistic gene expression analysis including tissue, cell-type and single cell level analysis. This project will provide novel insight about protective immunity against Mycobacteria. Gained knowledge will
guide development of better vaccines against tuberculosis.

Key words: Tuberculosis, zebrafish, protective immunity, Mycobacteria, transcriptomics

Main supervisor: Professor Olli Silvennoinen, Tampere University, olli.silvennoinen@tuni.fi,
https:/research.tuni.fi/molecular immunology

Other supervisor(s): Professor Heikki Hyöty, Tampere University heikki.hyoty@tuni.fi,
https://research.tuni.fi/virology/

Doctoral researcher: Vivian Kettunen

Pilot project description

Cytokines that mediate their signals via Janus kinases (JAKs, JAK1-3, TYK2) play an important role in the pathogenesis of autoimmune diseases, such as type-1 diabetes (T1D). T1D is caused by destruction of insulin-producing pancreatic β-cells by the immune system. Genetic and environmental factors are known to contribute to the disease, and enteroviruses (EV) have been recognized as key triggers of autoimmunity in T1D1. Cytokines can contribute to the pathogenesis of T1D by affecting the aberrant immune response towards the pancreatic β-cells, and also by regulating innate antiviral response and virus propagation in cells2. In this regard two cytokines are particularly important, IFN-α (mediated by JAK1/TYK2) and IFN-γ (JAK1/JAK2) are implicated in the initiation of T1D but this association is complex, and mechanisms are not known2.
Recently JAK inhibitors have emerged as promising agents in treatment of T1D. In early clinical or preclinical studies, baricitinib (JAK1/JAK2-inhibitor) and deucravacitinib (selective TYK2-inhibitor) have been demonstrated to preserve β-cell functions by currently unknown mechanisms3.
The project aims to define the role of cytokines and the effects of JAK inhibition in T1D pathogenesis and combines the long-term expertise of Molecular Immunology group on JAK kinases and their therapeutic targeting and Virology group on pathogenesis and prevention of T1D in preclinical and clinical studies.
1 Blum, Microorganisms, 2020, 8 :993; Vehik, Nat Med, 2019, 25:1865-1872.
2Lu, Clin Transl Immunol, 2020, 9:e1122.
3 Waibel, N Engl J Med, 2023, 389 :2140-2150; Dos Santos, Front Immunol, 2023, 14:1263926

Key words: Type 1 diabetes, JAK kinase, cytokine, interferon

Main supervisor: Prof. Anu Kauppinen, University of Eastern Finland, School of Pharmacy, anu.kauppinen@uef.fi, www.uef.fi/io

Other supervisor(s): Dr. Maria Hytti, University of Eastern Finland, School of Pharmacy, maria.hytti@uef.fi, www.uef.fi/io; Prof. Kai Kaarniranta, University of Eastern Finland and Kuopio University Hospital, kai.kaarniranta@uef.fi, www.kaarnirantalab.fi

Doctoral researcher: MSc Kiia Koivusalo

Pilot project description

Age-related macular degeneration (AMD) is a progressive eye disease and the leading cause of irreversible vision impairment among the elderly in developed countries. Inflammation is strongly associated with both dry and wet forms of advanced AMD, and retinal adaptive immune responses are dominated by T lymphocytes. The role of the complement system is also highlighted, especially since complement components contribute to the formation of extracellular deposits and promote the release of pro-inflammatory cytokines. Substitution of histidine by tyrosine (Y402H) in complement factor H (CFH) is one of the most well-known gene variants associated with AMD. Therapy options are scarce, and the progression of the disease cannot be controlled until the pathophysiology of AMD is known in more detail.

The retinal pigment epithelium (RPE) plays a crucial role in the pathogenesis of AMD, as its degeneration precedes the death of photoreceptor cells and thus the loss of central vision. Combined with reduced autophagy, oxidative stress perpetuates a vicious cycle that promotes the accumulation of waste material and dysfunctional mitochondria in the retina and induces inflammation. In this study, the intracellular events that induce inflammation in the RPE are related to the functions of immune cells accumulated in the retina due to the broken blood-retinal-barrier. The research is conducted exclusively using human cells. Cell lines (ARPE-19 and D407) are used for optimization and extensive validations, while sparingly available and more time-consuming iPSC-RPE cells and primary RPE cells are used to verify key findings. T cells and macrophages are isolated from blood samples of AMD patients and control subjects, and their responses to RPE-derived factors are studied using flow cytometry, biochemical tests and microscopy. Patient-specific cell lines are a step towards personalized medication.

Key words: age-related macular degeneration, inflammation, macrophage, neovascularization, retinal pigment epithelium, T cell

Main supervisor: Prof. Tuure Kinnunen, University of Eastern Finland, School of Medicine, tuure.kinnunen@uef.fi, https://uefconnect.uef.fi/en/translational-immunology-group/

Other supervisor(s): Dr. Liisa Kröger, Kuopio University Hospital, liisa.kroger@pshyvinvointialue.fi

Doctoral researcher: MSc Bella Lappalainen

Pilot project description

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood. It is a heterogeneous disease of likely autoimmune origin that is currently classified into seven different subtypes. The current classification of JIA, however, does not accurately reflect the biologically diverse background of the disease. Specifically, the true cause behind the different disease manifestations, including what types of immune cell play roles in the initiation and exacerbation of JIA, has yet to be fully elucidated. Hence, a better classification of the different subtypes of JIA via immune biomarkers may lead to a better understanding of the disease and thus how to treat it. Moreover, because of disease heterogeneity it is currently extremely difficult to predict who will benefit from the different types of expensive immunosuppressive biological drugs available and how long these medications need to be administered. Specifically, upon immunosuppressive treatment withdrawal >50% of the patients relapse within 12 months. This in turn, leads to increased morbidity and treatment costs.

In this doctoral dissertation project, we aim to detect differences in blood immune cell populations and inflammatory protein levels in blood samples from JIA patients compared to healthy age- and sex-matched controls, as well as in patients who have or have not relapsed after medication withdrawal. For these studies, we will use multicolor flow cytometry and the next-generation Olink proteomics platform. The project will increase knowledge of what immune cell subtypes and/or cytokines play a central role in JIA. Moreover, the research could help identify cellular or proteomic immune signatures in peripheral blood that could be used as biomarkers to better classify different JIA subtypes and/or could be used to evaluate the risk of disease relapse upon medication withdrawal.

Key words: autoimmunity, T cell, flow cytometry, proteomics, biomarker, juvenile idiopathic arthritis,

Doctoral researcher: Juho Nummelin

Main supervisor: Karita Haapasalo, University of Helsinki, karita.haapasalo@helsinki.fi, Inflammation and Infections Research Group

Doctoral researcher: Lilith Heiland

Pilot project description

Alzheimer’s disease (AD), the most common cause of dementia, is a complex age-dependent disease and no cure has been found so far. Hallmarks of AD include the formation of Aβ plaques in the extracellular space of the brain. However, these plaques are also present in the brains of individuals that have no indication of dementia, suggesting that Aβ alone is not responsible for triggering the development of AD but instead requires an inflammatory factor. The complement system, a crucial part of the innate immunity, plays an important role in the pathogenesis of AD. The findings of our research group at the University of Helsinki (UH) have shown that dysregulation of complement activation leads to accumulation Aβ and increased inflammation. Previous studies suggest that Aβ has antimicrobial activity and may play a role in the innate immune defence against neurotropic pathogens.  The preliminary data of our team has shown that Aβ shows target specificity in recognizing harmful invaders and that some neurotropic pathogens (Lyme disease Borrelia and Streptococcus pneumoniae) are able to evade Aβ-mediated killing.

The aim of this project is to understand the physical and pathophysiological role of Aβ in the central nervous system (CNS) and provide detailed insight into the importance of the innate immune system in maintaining homeostasis and protecting the brain during infection. An in vitro 3D tetraculture infection model will be used to study the effect of multiple interactions between Aβ, bacteria and immune molecules in a pathological microenvironment. An in vivo animal model and a unique set of meningitis patients will be analyzed to discover the key neuroinflammatory markers, and microbial and host factors, that cause spatial, temporal and functional changes in the immune response of the CNS.

Key words: Borrelia, amyloid-β, Alzheimer’s disease, Lyme Neuroborreliosis, 3D cell culture, Innate Immunity

Main supervisor: Pirta Hotulainen, Minerva Foundation Institute for Medical Research, Helsinki, pirta.hotulainen@helsinki.fi, https://minervainstitute.fi/research-groups/cellular-neuroscience/

Doctoral researcher: Jaan Korpikoski

Pilot project description

Transient peripheral inflammation can lead to persistent changes in the central nervous system (CNS) and behavior, but the exact mechanisms are still largely unknown. Peripheral inflammation is also a major risk factor for several CNS diseases, like Alzheimer’s disease, so it is pivotal to study this phenomenon more deeply. Our goal is to understand what happens in the CNS at different stages after the induction of peripheral inflammation and which are the correct time points and ways to prevent changes.

Hotulainen group is using a rheumatoid arthritis mouse model to study the mechanism of how inflammation travels from the periphery to the CNS and how that affects mouse behavior. In this model, the mice will develop transient arthritis in their joints, which will heal within one month. After that, the mice will not show any external signs of peripheral inflammation. Group will analyze peripheral inflammation-induced cellular changes in the CNS during and after inflammation and elucidate mechanisms leading to these changes. Special tasks of ImmuDoc student Jaan Korpikoski are to analyze inflammation markers from blood and brain tissue and to develop methods to analyze changes, especially utilizing AI-based image analysis technologies.

Key words: Inflammation, neurons, astrocytes, microglia, cytokines, image analysis

Main supervisor: Eliisa Kekäläinen, Docent, MD Ph.D, University of Helsinki and Helsinki University Hospital, eliisa.kekalainen@helsinki.fi, https://www.helsinki.fi/en/researchgroups/inborn-and-acquired-immunodeficiencies

Other supervisor(s): Pirkka Pekkarinen, Docent, MD Ph.D, University of Helsinki and Intensive care unit, Helsinki University Hospital, pirkka.pekkarinen@helsinki.fi

Doctoral researcher: Huai Hui Wong, huai.wong@helsinki.fi

Pilot project description

The aging of the immune system, termed immunosenescence, describes the decline and qualitative changes in immune responses. Due to influence from unknown environmental factors, immunosenescence varies greatly among individuals, with some experiencing it earlier than others. Currently, the role of immunosenescence in conditions like long COVID and during recovery from cardiac arrest remains largely unstudied. In both conditions, some individuals develop debilitating long-term symptoms such as fatigue and cognitive dysfunction, which could develop due to excessive or dysregulated inflammatory responses triggered by the acute illness. As life expectancy increases, it is important to enhance our understanding of how an aging immune system responds to various external challenges. In this PhD project, well-characterized study cohorts and their matched controls from Helsinki University Hospital would be analyzed to assess the patients’ immunological age using modern systems immunology methods. The outcomes of this project will broaden our understanding of immunosenescence and its impact on debilitating long-term symptoms following acute illnesses.

Key words: Immunosenescence, inflammaging, long COVID, cardiac arrest, aging, flow cytometry

Main supervisor: Docent of Immunogenetics Inkeri Lokki, University of Helsinki, Department of Bacteriology and Immunology, inkeri.lokki@helsinki.fi, https://researchportal.helsinki.fi/fi/persons/a-inkeri-lokki

Other supervisor(s): Professor of Immunology, MD Seppo Meri, University of Helsinki, Department of Bacteriology and Immunology, seppo.meri@helsinki.fi, https://www.helsinki.fi/en/researchgroups/complement-group#:~:text=The%20Complement%20group%2C%20headed%20by,tumor%20cells%20escape%20complement%20attack.

Doctoral researcher: MMSc Mari Humalajoki

Pilot project description

The thesis will explore clinical and cellular manifestations of human complement system dysfunction caused by deficiencies of the central complement component C3. The thesis will present a unique Finnish patient case of complete C3 deficiency and two probands with secondary C3 deficiencies, including a characterization of a novel loss-of-function mutation in Factor H. The thesis will explore how the immune system of these patients functions despite these severe deficiencies of innate immunity. The thesis aims to explore the novel functions of the complement system and the complosome in the context of C3 deficient individuals.

Key words:

Complement, Immunogenetics, C3 deficiency, Factor H, Innate immunity, Immunohealth

Main supervisor: Satu Mustjoki, Professor, MD, PhD, satu.mustjoki@helsinki.fi https://www.helsinki.fi/en/researchgroups/hematology-research-unit-helsinki

Other supervisor(s):

Sara Gandolfi, MD, PhD, sara.gandolfi@helsinki.fi https://www.helsinki.fi/en/researchgroups/hematology-research-unit-helsinki

Shady Adnan Awad, MD, PhD, shady.awad@helsinki.fi https://www.helsinki.fi/en/researchgroups/hematology-research-unit-helsinki

Doctoral researcher: Linnea Wartiovaara, MSc

Pilot project description

Immunotherapies harbor tremendous potential in cancer treatment, yet the treatment outcomes have remained modest due to reasons hypothesized to lie primarily in the tumor microenvironment. Enhancing natural killer (NK) cell responses against cancer has been a promising target of recent immunotherapy approaches, however only little is known about possible microenvironmental influences over NK cell functions.

The aim of this doctoral work is to investigate how somatic mutations and neighboring cells in the tumor microenvironment affect NK cells in the elimination of cancer cells in hematological malignancies and specifically characterize the immune microenvironment in pediatric B-cell acute lymphoblastic leukemia (B-ALL). These approaches are expected to discover factors for the enhancement of both native NK cell responses and novel NK-cell-based regimens in cancer treatment and improve pediatric B-ALL relapse prediction and treatment via understanding the immune composition at diagnosis.

Key words: Natural killer cell, immunotherapy, hematological malignancy, tumor microenvironment, somatic mutation, cancer

Doctoral researcher: Hele Haapaniemi

Main supervisor: Niina Sandholm, Folkhälsan Research Center and University of Helsinki, niina.sandholm@helsinki.fi http://www.finndiane.fi/

Other supervisors: Stefan Mutter, Folkhälsan Research Center and University of Helsinki, Stefan.mutter@helsinki.fi

Doctoral researcher: Soheila Akhondzadeh

Pilot project description

Diabetes impacts over 500 million people worldwide, leading to severe complications such as diabetic kidney disease (DKD), cardiovascular disease (CVD), and diabetic retinopathy (PDR). These complications lower the quality of life and increase healthcare costs. Early identification of individuals at risk is vital for prevention and effective treatment. Finland, with the highest incidence of Type 1 diabetes (T1D), the autoimmune form of diabetes, provides a unique setting for this research.

This ImmunoDocs pilot project focuses on subtype identification in individuals with T1D to better predict the risk of diabetic complications. Utilizing comprehensive multi-omics data from the Finnish Diabetic Nephropathy Study (FinnDiane), the project integrates genetic, clinical, proteomic, and epigenetic data to identify subgroups vulnerable to complications. We will utilize machine learning methods to cluster the T1D patients based on clinical and genetic data, including also the HLA haplotypes as the major genetic drivers of T1D, and examine their association with diabetic complications. In the subsequent studies we will use proteomic and epigenetic analyses to identify biomarkers and pathways characterizing the various identified subgroups, and will investigate their influence on diabetic complications. By integrating these multi-omics approaches, this project research aims to provide a comprehensive understanding of T1D heterogeneity, identifying biomarkers and mechanisms that can guide early prediction and personalized clinical care.

Key words: Type 1 diabetes, clustering, subgroups, genetics, proteomics, epigenetics

Main supervisor: Kari Vaahtomeri, Docent, Ph.D, University of Helsinki and the Wihuri Research Institute, kari.vaahtomeri@helsinki.fi, https://www.helsinki.fi/en/researchgroups/cell-communication/people

Doctoral researcher: Jeremia Saari

Pilot project description

My project focuses on lymphatic vessel growth and remodeling. The lymphatic system plays roles in the body’s immune surveillance and fluid circulation. Lymph nodes, found for instance in the neck, armpit and groin regions, make up the most conspicuous part of the system due to their tendency to swell during inflammation. Yet, another part of the lymphatic system, lymphatic vasculature, consist of blunt-ended capillary vessels that form dense networks, which merge into larger collector vessels that connect to the lymph nodes.

Lymphatic vessels cover vast areas of the body such as skin, lungs and the gut, i.e. interfaces of the body and the outside world. These surfaces make frequent contact with microbes, including harmful pathogens. Therefore, among the lymphatic vessels, specialized immune cells called dentritic cells patrol the tissue, sampling their surroundings, looking for molecular cues of pathogen presense. When such cues are found, dentric cells are programmed to take them to the lymph nodes for further recognition by other immune cells capable of lauching a targeted attack against the pathogen in question. In the crucial step of dentritic cell migration to the lymph node, the lymphatic vasculature functions as a recruitment and transportation network.

Thus, my aim is to study the mechanisms behind lymphatic vessel network “expansion”, that is, growth that increases the network density. While expansion of mature lymphatic vessels is known to happen under inflammation, the cell and molecular level details of the process are not currently understood. Previous findings from our laboratory show that during development, side-branching of lymphatic vessels is needed for reaching optimal network density. My project delves deeper into the process of side-branching, seeking to find out how it is controlled by co-operation between the cells that make up the lymphatic vasculature. I believe this research will support future endevours into harnessing the lymphatic system to treat inflammation-associated disease.

Key words: Lymphatic system – lymphatic endothelium – immune surveillance – lymphatic vessel remodeling

Main supervisor: Kari Vaahtomeri, The University of Helsinki and the Wihuri Research Institute, kari.vaahtomeri@helsinki.fi, https://www.helsinki.fi/en/researchgroups/cell-communication

Doctoral researcher: Maria Saario, maria.tm.saario@helsinki.fi

Pilot project description

The human immune system has to main subsystems: the unspecific innate immune system, and the pathogen-specific adaptive immune system. While both systems are required to fight infectious diseases, the cells of the adaptive immune system are essential for regonition and, subsequent, abolishment of pathogenic invaders and tumors, and also, to elicit vaccination-induced pathogen-specific protection. The adaptive immune system is activated by professional antigen presenting cells (APCs), such as dendritic cells (DCs), which present antigens and activate T cells in the secondary lymphoid organs. Once activated, the T cells migrate to inflamed tissue to recognize and eliminate pathogens.

Recent years have revolutionized our understanding of the role of the lymphatic system in the control of adaptive immunity. It has become evident that lymphatic endothelium, i.e. the lining of the lymphatic vessels and lymph nodes, is essential for launching adaptive immune response via trafficking of immune cells and antigens. Moreover, the lymphatic endothelium has been shown to have direct role in immunomodulation. This role is facilitated via LEC-mediated internalization of soluble antigens from the lymph. LECs can utilize the internalized antigens, and i) transfer the antigens to DCs for comprehensive T cell activation, or ii) present the antigens straight to T cells, to promote tolerance. Through these functions, LECs have been shown to play a role in the maintenance of peripheral T cell tolerance and, conversely, the creation of stronger secondary immune response due to stimulation of T memory cell generation. Despite the importance of lymphatic endothelial immunomodulation, the associated molecular mechanisms remain poorly characterized. In my PhD project, I investigate the role of lymphatic endothelium in control of adaptive immunity.

Key words: adaptive immunity, lymphatic system, lymphatic endothelium, dendritic cell, T cell