Project description
Countering cancer cells' evasive maneuvers
T-cells play a significant role in immunity. Cancer cells can stay alive and flourish by avoiding their activation. T-cell lymphomas are a diverse group of non-Hodgkin lymphomas that can be particularly aggressive and effective treatments are lacking. A promising route may be the inhibitory immune receptor PD-1 found on T-cells. When healthy cells that express its ligand bind to PD-1, T-cells know to leave them alone. The EU-funded T-NHL SUPRESSORS project is investigating how cancer cells might use PD-1 ligands to avoid initiation of an immune response. Enhancing understanding of this powerful survival mechanism in T-cell lymphomas could advance the development of desperately-needed immunotherapy for the most aggressive forms.
Objective
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 GrantHost institution
81675 Muenchen
Germany