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MRNA stability factor HuR promotes immune evasion in pancreatic ductal adenocarcinoma

ABSTRACT: The limited infiltration of tumor-specific T cells into the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) is hypothesized to limit immunotherapy responses. The RNA-binding protein, HuR (ELAVL1), is over-abundant in PDAC, and its expression negatively correlates with T cell infiltration. In the immunocompetent Kras-p53-Cre (KPC) model, we found HuR depletion impairs tumor growth. To investigate the impact of the immune cells on tumor growth, we analyzed the infiltrated immune population in tumors and found that HuR-depleted tumors had increased T cell infiltration and activation. Mechanistically, HuR mediated stabilization of mTOR pathway and enhanced PDAC nutrient consumption, which impaired local T-cell antitumor function. We found that HuR suppression of antitumor immunity has profound consequences, as HuR-deficient tumors are sensitive to immune checkpoint blockade, while isogenic, wildtype tumors are resistant. These findings describe a novel role of HuR in PDAC facilitating tumor immune suppression in the PDAC TME by inhibiting T cell infiltration and function.

ORGANISM(S): Mus musculus

PROVIDER: GSE287307 | GEO | 2025/02/05

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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MRNA stability factor HuR promotes immune evasion in pancreatic ductal adenocarcinoma

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