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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE261694 | GEO | 2026/02/19

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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

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