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.

Project description:Pancreatic ductal adenocarcinoma (PDAC) displays a poor response to immunotherapy. This poor response is predominantly attributed to the highly immunosuppressive tumor microenvironment (TME), characterized by a scarcity and dysfunction of infiltrating CD8+ T cells. Epigenetic regulators have recently been implicated in immune escape and immunotherapy sensitivity, presenting an appealing approach for directly targeting epigenetic factors or combining epigenetic therapies with immunotherapy in PDAC. Our study is the first to delineate the regulatory function of the epigenetic factor Sin3B in the tumor immune microenvironment (TIME) of PDAC. Using murine PDAC models, we discovered that intrinsic Sin3B loss in tumor cells reshapes the TIME, manifested by increased CD8+ T cell infiltration into tumors through enhanced secretion of CXCL9 and CXCL10. This was accompanied by an increase in the cytotoxicity of CD8+ T cells, as evidenced by elevated Granzyme B (GzmB) and IFNγ production. Furthermore, Sin3B-deficient tumor cells exhibited heightened secretion of CXCL9/10 in response to IFNγ, creating a positive feedback loop via the CXCL9/10-CXCR3 axis and thus intensifying immune response against PDAC. Additionally, loss of Sin3B increased PDAC susceptibility to anti-PD1 therapy in mice. Corroborating our findings in the mouse model, analysis of human PDAC samples demonstrated a significant inverse correlation between Sin3B levels and both CD8+ T cell presence and CXCL9/10 expression. Notably, PDAC patients with lower Sin3B expression exhibited a more favorable response to anti-PD1 therapy. Concerning the mechanism, we systematically uncovered the extensive epigenetic regulation employed by Sin3B loss via the modulation of H3K27Ac redistribution in PDAC cells. Sin3B deficiency resulted in an uptick of H3K27Ac peaks concentrated in the promoter and enhancer regions. Under the treatment of IFNγ, Sin3B loss leads to the enrichment of H3K27Ac peaks in promoter regions of ISG-related genes such as CXCL9 and CXCL10, thereby boosting their expression. Collectively, our research outcomes propose a potential target for enhancing the accessibility of cytotoxic T cells to the tumor site and improving immunotherapy in the challenging landscape of PDAC.

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CD137 agonism enhances anti-PD1 induced activation of clonally expanded CD8+ T cells in a neoadjuvant pancreatic cancer clinical trial

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