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Understand co-stimulation of T cells by dendritic cells to design better cancer immunotherapies

ABG-116654 Stage master 2 / Ingénieur 6 mois Eligible to Erasmus/AMI funding
19/09/2023
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Biotechnologie Institut Thurgau
Kreuzlingen Suisse
  • Biologie
  • Biotechnologie
  • Santé, médecine humaine, vétérinaire
immunological synapse, immune response, immunology, T cells, dendritic cells, tumor necrosis factor receptor, tumor, immune synapse, microscopy

Établissement recruteur

The Biotechnology Institute Thurgau (BITg) is an academic research institution located in Kreuzlingen, Switzerland. The institute focuses on application-oriented basic research in the field of tumor biology, immunology and cell biology.

The Foundation for Science and Research of the Canton Thurgau (Thurgauische Stiftung für Wissenschaft und Forschung, TSWF), founded BITg in 1999 in close collaboration with the University of Konstanz. The Thurgovian Foundation still supports the institute financially. Academically, BITg is associated with the University of Konstanz and affiliated with the Department of Biology. The Institute also participates in the university’s lecturing and academic training programmes. Since 2004 BITg is recognized as a Swiss research institution of national relevance and it is supported by the State Secretariat for Education, Research and Innovation.

Description

Context

Boosting the natural immune response against cancer cells through immunotherapy has revolutionised the therapeutic options to treat cancer. The three arms of cancer immunotherapy include 1) immune checkpoint blockade, 2) adoptive transfer of chimeric antigen receptor (CAR) T cells and cancer vaccines. However, only a relatively small percentage of patients respond to these therapies, which highlight the need for improvement.

T cells, and in particular cytotoxic CD8+ T cells (CTLs), are the armed wing of the immune response against developing tumours and consequently the focus of current immunotherapy approaches. CTLs need first to be instructed on what to do. This is achieved by dendritic cells, which cross-present antigens, thereby initiating the CTL response against tumour cells. Dendritic cells are present in tumour-draining lymph nodes, but also at the tumour microenvironment (TME), where they play an essential role in re-stimulating CTLs. Hence, dendritic cells are critical to promote tumour infiltration of CTLs and cancer cell killing. A better understanding their anti-tumour potential is needed to design novel or improve current immunotherapy approaches.

Co-stimulatory or inhibitory molecules at the surface of dendritic cells is an essential part of the signal transmitted to T cells during priming or re-stimulation. Receptors of the tumour necrosis factor receptor (TNFR) superfamily constitute a large proportion of T cell co-stimulatory receptors, and their triggering potentiates the T cell response by promoting cytokine secretion, cell proliferation and survival. As such they represent an important avenue to improve current immunotherapeutic strategies. Pre-clinical studies have shown that stimulation of these receptors amplifies the effects of current cancer treatments. Similarly, third generation CARs include the intracellular domains of these receptors, with distinct improvement on the capacity of engineered CTLs to kill tumour cells. Despite promising results in cancer immunotherapies, the mechanism of co-stimulation of T cells by dendritic cells through co-stimulatory TNFRs remains poorly understood. We know for instance nothing about how these receptors are presented by dendritic cells to T cells within the immunological synapse, which mediates the interaction between these two cell types. Our group has developed microscopy-based approaches to visualise the spatial organisation of co-stimulatory proteins at the immunological synapse of dendritic cells. Using these approaches, we have shown that CD40 and CD70 distributions is non-random at the dendritic cell side of the immunological synapse. We have further indication that the engagement of their cognate ligand leads to formation of specialised dendritic cell synapses.

 

 

Project

The aim of the proposed project is to extend these data and build a comprehensive understanding of the dynamics and spatial organisation of CD40 and CD70 at the dendritic cell synapse. We will use bone marrow derived dendritic cells (BMDCs) or dendritic cell lines expressing CD40 or CD70 tagged with fluorescent proteins to determine how they are recruited and organised at the immunological synapse. This will involve methods such as single-molecule and live cell microscopy. The project further involves micropatterned activating surfaces to understand how dendritic cells distributes these receptors between several synapses when engaging more than one T cell. Finally, the project will also investigate how engagement of these receptors regulates signalling pathways involved in synapse formation.

Profil

  • Student of Master 2/ Last year Engineering degree
  • English speaker required
  • Technical knowledge in cell culture, other techniques can be learned during the internship.

 

 

Prise de fonction

Dès que possible
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