mRNA stability factor HuR promotes immune evasion in pancreatic ductal adenocarcinoma
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. Overall design: RNA-seq profiling of wildtype KPC8069 cells and their HuR knockout derivatives.