Agonistic GITR therapy in combination with chemotherapy to promote tumor immunity in pancreatic ductal adenocarcinoma

Despite advances immunotherapy has shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment (TME) of PDAC is profoundly immunosuppressive, creating a barrier to effective antitumor immune responses. This work highlights the emerging role of co-stimulatory molecules, particularly the type I transmembrane protein glucocorticoid-induced TNFR-related protein (GITR), in modulating the immunosuppressive TME of PDAC. By enhancing T cell activation and effector functions, GITR holds promise as a target for novel immunotherapeutic strategies in PDAC.Here, we show that GITR is highly expressed and further increased by neoadjuvant chemotherapy in human PDAC and a murine PDAC model. GITR activation reduced the number of regulatory T cells and increased the number of activated cytotoxic effector lymphocytes in the TME, thereby reducing tumor growth and prolonging survival. Moreover, spatial transcriptomic analysis showed GITR expression primarily in lymphocytes in proximity to tumor cells in human PDAC. Altogether, our data present GITR as a potential novel target for neoadjuvant treatment that could be combined with standard chemotherapy. Overall design: We used murine tumors grown from Pan02 cancer cells injected subcutaneously and harvested 14 day after injection. Three tumors for each condition were pooled before sequencing. One sample contains data from tumors grown in mice which received intraperitoneal injections of PBS on days 7 and 11 post cancer cell injection, and the other sample contains data from tumors grown in mice which received intraperitoneal injections of agonistic anti-GITR monoclonal antibody (DTA-1) on days 7 and 11 post tumor cell injection as well.