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Structural basis for the therapeutic efficiency of optimal-affinity T cell receptors

Project description

A 3D snapshot of antigen recognition could pave the way to enhanced immunotherapy

Cancer immunotherapy is gaining a lot of interest for its potential to boost a person's own immune system to attack tumours, but treatment efficacy and patient response have so far been unpredictable. Among the most important cells in the immune system are the T-cells that mediate adaptive immunity via their T-cell receptors (TCRs). TCRs recognise invaders from small molecules (peptides) presented to them by so-called antigen-presenting cells via major histocompatibility complex (MHC) proteins. This process is extremely specific in vivo and harnessing this specificity could provide a breakthrough in immunotherapy. The EU-funded TCRabX project is using high-tech methods to study the detailed 3D structures of TCRs bound to MHC proteins to identify the TCR contact regions.

Objective

Demographic change includes population ageing, and incidence rates begin to increase for many types of cancer in middle-aged and elderly people. Traditional cancer treatment includes surgery, chemotherapy, and radiation therapy, while tumour immunotherapy by T cell receptor (TCR) gene transfer represents an alternative form of treatment. The transfer of tumour-specific TCR genes into patient’s peripheral blood lymphocytes targets cancer specifically and effectively. But while patient-derived low-affinity TCRs do not show therapeutic activity, optimal-affinity TCRs, as isolated from newly-generated antigen-negative humanized mice with a diverse human TCR repertoire, can effectively delay tumour regression. X-ray crystallography is a powerful tool of structural biology, which helps researchers to identify the three-dimensional (3D) structures of biological macromolecules such as TCRs complexed to their cognate peptide-loaded major histocompatibility complex (pMHC) molecules. Recent research uncovered the docking topologies of naturally selected TCRs, but therapeutically efficient optimal-affinity TCRs recognizing tumour-associated self-antigens, have not been analysed to date. The exceptional specificity of TCRs is determined by three complementarity-determining regions (CDRs) of the TCR alpha- and beta-chains. Biomedical research on TCR gene therapy and design of future clinical trials will hugely benefit from the identification of CDR-mediated contact points made between therapeutic TCRs and the pMHC on their target cells. TCRabX is an interdisciplinary research project investigating the 3D structures of 13 TCRs complexed to MHC-I or MHC-II, respectively. It connects innovative clinical immunology research in Berlin/Germany and world-class structural biology research in Melbourne/Australia. The proposed research will enhance the health and well-being of citizens in Europe and worldwide by supporting the advancement of cancer immunotherapy approaches.

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Coordinator

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Net EU contribution
€ 264 110,40
Address
Chariteplatz 1
10117 Berlin
Germany

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Region
Berlin Berlin Berlin
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00

Partners (1)