Description du projet
Contrer les manœuvres d’évitement des cellules cancéreuses
Les cellules T jouent un rôle important dans l’immunité. Les cellules cancéreuses peuvent rester en vie et prospérer en évitant leur activation. Les lymphomes à cellules T constituent un groupe diversifié de lymphomes non hodgkiniens particulièrement agressifs et sans traitements efficaces. Une voie prometteuse pourrait être le récepteur immunitaire inhibiteur PD-1 présent sur les cellules T. Lorsque les cellules saines qui expriment leur ligand se lient à PD-1, les cellules T savent qu’elles ne doivent pas interférer. Le projet T-NHL SUPRESSORS, financé par l’UE, étudie comment les cellules cancéreuses pourraient utiliser des ligands de PD-1 afin d’éviter le déclenchement d’une réponse immunitaire. Une meilleure compréhension de ce mécanisme de survie puissant des lymphomes à cellules T pourrait faire avancer le développement de l’immunothérapie indispensable aux formes les plus agressives.
Objectif
T cell non-Hodgkin lymphomas (T-NHLs) are highly aggressive malignancies that are largely resistant to conventional therapies. T-NHLs remain significantly understudied, and their molecular pathogenesis is still not well defined. Comprehensive analysis of mature T-cell lymphomas has identified multiple gain-of-function mutations in T-cell receptor (TCR) signaling molecules as an overarching hallmark of T-NHL sub-entities. Under physiological conditions, these molecules control the expansion, survival and effector function of antigen sensing T cells for host defense. Presumably, the oncogenic TCR signaling variants in lymphoma enforce these TCR programs in a constitutive manner and thereby drive continuous proliferation and expansion of the malignant clone. However, experimental in vivo evidence for this hypothesis is still limited, and the negative regulatory tumor suppressor mechanisms that can counteract oncogenic T cell signaling remain largely undefined. We recently identified the inhibitory immune receptor PD-1 as a key haploinsufficient tumor suppressor in T-cell lymphoma that is inactivated in up to 30% of human cases. The overall goal of this proposal is to comprehensively model and dissect T-cell lymphomagenesis driven by oncogenically enforced T-cell receptor pathways and to identify the PD-1 dependent and independent tumor suppressor mechanisms that inhibit these events. We will additionally explore the functions of new negative regulators within the PD-1 pathway or related pathways in antigen-mediated T cell activation. We expect that our results will provide fundamental new insights into the molecular pathomechanisms of highly aggressive T cell cancers and additionally lead to the identification of new negative regulators of antigen-mediated T cell activation.
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ERC-ADG - Advanced GrantInstitution d’accueil
81675 Muenchen
Allemagne