Description du projet
Connaissances mécanistes de l’infiltration des lymphocytes T dans les tumeurs
Les lymphocytes T sont capables de reconnaître et d’attaquer les cellules tumorales, générant ainsi une immunité contre le cancer. Cela étant, les tumeurs et leur microenvironnement immédiat ont développé des mécanismes biochimiques et physiques qui limitent l’accès aux lymphocytes T et leur procurent une résistance à la plupart des traitements disponibles. Financé par le Conseil européen de la recherche, le projet DRILL entend déterminer les mécanismes de migration des lymphocytes T vers les tumeurs en concentrant ses recherches sur la production de chimiokines dans le microenvironnement tumoral et sur la capacité inhérente des lymphocytes T à infiltrer les tumeurs. Ses résultats permettront de mieux comprendre la régulation de l’infiltration des lymphocytes T dans les tumeurs et, partant, d’améliorer les immunothérapies à base de lymphocytes T pour les tumeurs solides telles que l’adénocarcinome canalaire (pancréas).
Objectif
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.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
ERC - Support for frontier research (ERC)Institution d’accueil
69120 Heidelberg
Allemagne