Descrizione del progetto
Contrastare le manovre evasive delle cellule tumorali
Le cellule T svolgono un ruolo significativo nell’immunità. Le cellule tumorali possono sopravvivere e prosperare evitando la loro attivazione. I linfomi a cellule T sono un gruppo diversificato di linfomi non Hodgkin che possono essere particolarmente aggressivi e per i quali mancano trattamenti efficaci. Una via promettente potrebbe essere il recettore immunitario inibitorio PD-1 trovato sulle cellule T. Quando le cellule sane che esprimono il proprio ligando si legano al PD-1, le cellule T sanno di dover lasciarle sole. Il progetto T-NHL SUPRESSORS, finanziato dall’UE, sta studiando come le cellule tumorali potrebbero utilizzare i ligandi PD-1 per evitare l’avvio di una risposta immunitaria. Migliorare la comprensione di questo potente meccanismo di sopravvivenza nei linfomi a cellule T potrebbe far progredire lo sviluppo dell’immunoterapia disperatamente necessaria per le forme più aggressive.
Obiettivo
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.
Campo scientifico
Parole chiave
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Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
81675 Muenchen
Germania