Project description
Mechanistic insight into T cell infiltration into tumours
T cells have the potential to recognise and attack tumour cells, generating anti-cancer immunity. However, tumours and their immediate microenvironment have evolved biochemical and physical mechanisms that restrict access to T cells and also resist most available therapies. Funded by the European Research Council, the DRILL project aims to delineate the mechanisms of T cell migration to tumours by focusing on chemokine production in the tumour microenvironment and the inherent ability of T cells to infiltrate tumours. Results will help understand how T cell tumour infiltration is regulated, thereby advancing T cell-based immunotherapies for solid tumours such as pancreatic ductal adenocarcinoma.
Objective
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.
Fields of science
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
ERC - Support for frontier research (ERC)Host institution
69120 Heidelberg
Germany