Descripción del proyecto
Conocimientos mecanicistas sobre la infiltración de linfocitos T en tumores
Los linfocitos T son capaces de reconocer y atacar a las células tumorales, con lo que se genera una inmunidad contra el cáncer. Sin embargo, los tumores y su microentorno inmediato han desarrollado mecanismos bioquímicos y físicos que restringen el acceso a los linfocitos T y también resisten a la mayoría de los tratamientos disponibles. El equipo del proyecto DRILL, financiado por el Consejo Europeo de Investigación, pretende determinar los mecanismos de migración de los linfocitos T a los tumores centrándose en la producción de quimiocinas en el microentorno tumoral y en la capacidad inherente de los linfocitos T para infiltrarse en los tumores. Los resultados ayudarán a comprender cómo se regula la infiltración tumoral de linfocitos T, lo cual permitirá avanzar en las inmunoterapias basadas en linfocitos T para tumores sólidos como el adenocarcinoma ductal pancreático.
Objetivo
Cancer immunotherapies that leverage T cell activities are transforming cancer treatment. Currently, enormous effort has been devoted to empowering T cells to recognize and attack tumor cells. In contrast, the trafficking of T cells into tumors, a crucial prerequisite and limiting factor for effective T cell–tumor cell interactions, receives relatively less attention while at the same time being poorly understood. This is due to the complex and dynamic nature of T cell trafficking and the lack of model systems that allow function-based systematic investigation of the specific process.
This proposal integrates innovative functional genomics into physiologically relevant models that recapitulate two essential steps in the migration of effector T cells into tumors to investigate i) chemokine production in the tumor microenvironment (TME) and ii) chemotactic infiltration of T cells into tumors. Here we focus on one of the most devastating cancers, pancreatic ductal adenocarcinoma (PDAC), because it poses considerable physical and biochemical barriers that restrict the access of effector T cells to tumor cells and substantially resists all available therapies.
We will 1) elucidate the (co)regulatory mechanisms of the expression of chemokines that direct T cell recruitment and exclusion. In parallel, we will 2) develop model systems to systematically reveal cell-intrinsic determinants in T cells that influence their capability to infiltrate tumors. Finally, we will 3) evaluate whether pharmacological or genetic targeting of the modulators of T cell trafficking improves T cell-based cancer immunotherapies.
Collectively, this project will deliver fundamental insight into the mechanisms that regulate T cell trafficking into tumors and may yield novel strategies to broaden or increase the efficacy of the current cancer immunotherapies.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
ERC - Support for frontier research (ERC)Institución de acogida
69120 Heidelberg
Alemania