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

Descrizione del progetto

Un’istantanea 3D di riconoscimento degli antigeni potrebbe aprire la strada a una immunoterapia migliorata

L’immunoterapia antitumorale sta acquistando molto interesse per il proprio potenziale nel rafforzare il sistema immunitario di una persona nell’attaccare i tumori, ma l’efficacia del trattamento e la risposta del paziente sono stati fino ad oggi imprevedibili. Fra le cellule più importanti nel sistema immunitario si annoverano le cellule T che mediano l’immunità adattativa attraverso i loro ricettori delle cellule T (T-Cell Receptors, TCR). I TCR riconoscono gli invasori da piccole molecole (peptidi) che vengono loro presentate dalle cosiddette cellule che presentano antigeni attraverso proteine del complesso maggiore di istocompatibilità (Major Histocompatibility Complex, MHC). Tale processo è estremamente specifico in vivo e lo sfruttamento di tale specificità potrebbe condurre a una rivoluzione nell’immunoterapia. Il progetto TCRabX, finanziato dall’UE, sta utilizzando metodi ad alta tecnologia per studiare le dettagliate strutture 3D del legame dei TCR alle proteine dell’MHV, al fine di identificare le regioni di contatto dei TCR.

Obiettivo

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.

Coordinatore

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Contribution nette de l'UE
€ 264 110,40
Indirizzo
Chariteplatz 1
10117 Berlin
Germania

Mostra sulla mappa

Regione
Berlin Berlin Berlin
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 264 110,40

Partner (1)