Projektbeschreibung
Mechanistischer Einblick in die Infiltration von T-Zellen in Tumore
T-Zellen bergen das Potenzial, Tumorzellen zu erkennen und anzugreifen und so eine Immunität gegen Krebs zu erzeugen. Tumore und ihre unmittelbaren Mikroumgebungen haben jedoch biochemische und physikalische Mechanismen entwickelt, die den Zugang zu T-Zellen einschränken und auch den meisten verfügbaren Therapien widerstehen. Das vom Europäischen Forschungsrat finanzierte Projekt DRILL zielt darauf ab, die Mechanismen der T-Zell-Migration zu Tumoren zu beschreiben, indem es sich auf die Chemokin-Produktion in der Tumormikroumgebung und die inhärente Fähigkeit von T-Zellen zur Infiltration von Tumoren konzentriert. Die Ergebnisse werden dazu beitragen, zu verstehen, wie die T-Zell-Tumorinfiltration reguliert wird, und dadurch T-Zell-basierte Immuntherapien für solide Tumoren wie das duktale Adenokarzinom der Bauchspeicheldrüse voranbringen.
Ziel
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.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
ERC - Support for frontier research (ERC)Gastgebende Einrichtung
69120 Heidelberg
Deutschland