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Loss of ADAR1 in tumor cells activates cDC1s and sensitizes pancreatic cancer to immunotherapy

ABSTRACT: Pancreatic cancer is notoriously resistant to immunotherapy, primarily due to inadequate antigen presentation and the exclusion of immunogenic cells from the tumor microenvironment. Strategies to enhance antigen presentation and promote the infiltration of cytotoxic CD8+ T cells may improve the efficacy of immunotherapy in pancreatic cancer. In this study, we show that ADAR1 is overexpressed in pancreatic cancer, and higher ADAR1 expression correlates with poorer survival outcomes in patients. Depletion of ADAR1 in tumor cells leads to an accumulation of endogenous double-stranded RNA (dsRNA), which triggers the MDA5-mediated type I interferon (IFN) response and results in excessive IFNβ production. Tumor-derived IFNβ then promotes the recruitment and activation of cDC1s, thereby enhancing CD8+ T cell infiltration and activation, and ultimately sensitizing pancreatic cancer to CD8+ T cell-based immunotherapy. These findings suggest that combining ADAR1 inhibition with immunotherapy may offer a promising therapeutic strategy for pancreatic cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE289275 | GEO | 2025/04/11

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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Loss of ADAR1 in tumor cells activates cDC1s and sensitizes pancreatic cancer to immunotherapy

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