Call for Applications Autumn – CLOSED

Info for the Applicant

The ImmuDocs Doctoral Education Pilot offers 59 Doctoral Researcher positions in three calls in 2024 for a 3-year period in the fields of immunology, immunology-based drug development, and immunology-based diagnostics. Research conducted within the ImmuDocs projects can be basic, translational, and/or clinical.

There are three application periods for these positions. In the first call in April, we were seeking 29 Doctoral Researchers for positions starting on 1 August 2024. In this first autumn call, we have 20 positions starting on 1 January 2025. The second autumn call will be announced later.

Autumn application periods: 

First Autumn Call: 26.8.-24.9.2024

Second Autumn Call: 14.10.- 28.10.2024 (subject to change)

Note! To be eligible for these positions, an applicant’s study right for a doctoral degree must not have been granted earlier than 1 November 2023. If the applicant does not have the right to study for a doctoral degree at the University of Turku, they must apply for a right to study for a doctoral degree during the application period in 28.10.-8.11.2024.

What are the objectives of the ImmuDocs Doctoral Education Pilot? 

The ImmuDocs Doctoral Education Pilot aims to expand the pool of immunology experts in Finland, responding to clear national and European demand for trained immunologists in various sectors such as business, universities, and healthcare.

The ImmuDocs Pilot refines guidance practices and implements several key actions to significantly reform doctoral education. These include improving the feasibility of the Doctoral Researchers’ research plan, providing a clear, personalised, and structured study plan to be executed within a specified timeframe, ensuring effective supervision, streamlining administrative processes, and enhancing motivation and support for successful graduation. Both Doctoral Researchers and their supervisors must be committed to these new practices before entering the programme.

We aim to enhance the mobility of Doctoral Researchers by facilitating their movement between universities and companies and encouraging Doctoral Researchers to explore diverse career paths in research. This approach is intended to increase employment opportunities for Doctoral Researchers across a wide array of sectors in society, including but not limited to the healthcare industry, academia, public healthcare, and entrepreneurship.

What is taught in the ImmuDocs Doctoral Education Pilot? 

The ImmuDocs Pilot aims to ensure that, upon completion of the studies Doctoral Researchers: 

  • Have acquired extensive knowledge of modern and applied immunology, developed skills to critically interpret research data, and master key immunological methods. 
  • Thoroughly understand the impact of immunology on the economy and society. 
  • Have a clear understanding of the entire lifecycle of immunology-based diagnostics and drug discovery, including all essential steps from initial invention to clinical application. 
  • Communicate their research to the scientific community and the public.
  • Know which career paths are available for immunologists after obtaining a doctoral degree.

Applicants: Select the suitable pathway and ImmuDocs project(s) for you, and apply for a funded ImmuDocs Doctoral Researcher position

PATHWAY 1:  The applicant applies for specific project(s) provided by the ImmuDocs supervisors and selects a maximum of three projects in order of priority. A list of the projects is presented below.   

Eligibility criteria: The applicant has completed a relevant higher university degree or the applicant’s stage of studies allows the candidate to be awarded a study right for a doctoral degree before December 3 (Faculty of Medicine) or November 15 (Faculty of Technology and Faculty of Science).

PATHWAY 2: The applicant applies via an internal call (only available for applicants with access to the University of Turku intranet) for the funded position with the research plan of the ImmuDocs Pilot project. A list of the projects is presented below.

Eligibility criteria: The applicant is experienced with the defined project, and the applicant’s study right for a doctoral degree must not have been granted earlier than 1 November 2023. Moreover, the applicant has completed a relevant higher university degree, or the applicant’s stage of studies allows the candidate to be awarded a study right for a doctoral degree before December 3 (Faculty of Medicine) or November 15 (Faculty of Technology and Faculty of Science).

Please read in more detail how to apply for doctoral training at the University of Turku at the following link: How to apply for doctoral training at the University of Turku

PATHWAY 1:

A list of ImmuDocs Doctoral Education Pilot projects seeking candidates through an open call for applications. 

1. Impact of the innate immune system on target organ integrity in multiple sclerosis, Principal Supervisor: Laura Airas

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

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

2. Dendritic cell chemotaxis and gradient generation in changing tissue environment, Principal Supervisor: Jonna Alanko

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/


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

3. Uncovering mechanisms affecting waning vaccine-induced immunity against Bordetella pertussis, Principal Supervisor: Qiushui He

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

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

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

4. Exosomes and circulating leukocyte-born microbial DNA as drivers of autoimmunity and sources of biomarker discovery in systemic lupus erythematosus (SLE), Principal Supervisor: Arno Hänninen

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

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

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.

5. Novel approaches to immune monitoring and biomarker discovery in systemic lupus erythematosus (SLE), Principal Supervisor: Arno Hänninen

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/

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 Blymphocytes; TLRligands; singlecell RNA sequencing; 16S RNA sequencing

6. In-vivo Characterization of Pericoronary Local Inflammatory Activity in Atherosclerosis, Principal Supervisor: Juhani Knuuti

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

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

7. Changes in human immune cells associated with the development of type 1 diabetes, Principal Supervisor: Riitta Lahesmaa

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/;

Omid Rasool, PhD, Senior Researcher, email address, omid.rasool@utu.fi; https://bioscience.fi/research/molecular-systems-immunology/profile/

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

8. Mechanisms of antigen presentation in B cells - the role of Septin cytoskeleton, Principal Supervisor: Pieta Mattila

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/

 

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

9. Building blocks for computational immunology: Artificial intelligence based integrative analysis of histology and spatial proteomics, Principal Supervisor: Pekka Ruusuvuori

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):

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

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

Dr. Otto Kauko, Turku Bioscience, University of Turku, otto.kauko@utu.fi

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

10. In vitro assay and AI-assisted tools for improved characterization of anti-tumor immune response in bladder cancer, Principal Supervisor: Pekka Taimen

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) (public):

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/

 

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

11. Combined single-cell imaging and proteomic analysis to unveil human myeloid cell heterogeneity, Principal Supervisor: Akira Takeda

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

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

12. Three-dimensional streptavidin base layer as generic approach to improved antibody binding capacity and reactivity on solid-phase immunoassays, Principal Supervisor: Tero Soukka

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

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, pointofcare testing, streptavidin, antibody immobilization, protein adsorption

 

PATHWAY 2:

A list of projects for which applicants can apply via an internal call (accessible only to those with access to the University of Turku intranet).

  1. Targeting type 2 innate lymphoid cells to treat inflammation and fibrosis in lymphedema, Principal Supervisor: Pauliina Hartiala
  2. CRISPR screening of primary human macrophages to discover novel druggable regulators of antitumor effector functions, Principal Supervisor: Maija Hollmén
  3. Dual-targeting of myeloid malignancies and their tumor microenvironment with bexmarilimab, Pricipal Supervisor: Maija Hollmén
  4. Retinal Inflammation: the role of ATP-adenosine pathway, Principal Supervisor: Sirpa Jalkanen
  5. Identifying immune mediators of osteoarthritis pain, Principal Supervisor: Tapio Lönnberg
  6. Embryonic macrophages in brown adipose tissue development and function, Principal Supervisor: Pia Rantakari
  7. Non-invasive monitoring of inflammation and fibrotic activity in inflammatory bowel disease with molecular imaging, Principal Supervisor: Anne Roivainen
  8. Fibroblastic reticular cells in immunology: new regulators, new locations, Principal Supervisor: Marko Salmi