mRNA stability factor HuR promotes immune evasion in pancreatic ductal adenocarcinoma

The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by a limited infiltration of tumor-specific T cells and anti-tumor T cell activity. Extracellular factors in the PDAC TME have been widely reported to mediate immune suppression, but the contribution from tumor-intrinsic factors is not well understood. The RNA-binding protein, HuR ( ELAVL1 ), is enriched in PDAC and negatively correlates with T cell infiltration. In an immunocompetent Kras-p53-Cre (KPC) orthotopic model of PDAC, we found that genetic disruption of HuR impaired tumor growth. Importantly, we found that HuR depletion in tumors enhanced both T cell number and activation states. Mechanistically, HuR mediated the stabilization of mTOR pathway transcripts, and inhibition of mTOR activity rescued the impaired function of local T cells. Phenotypically, we found that HuR induced T-cell suppression in PDAC, as HuR depletion sensitize PDAC tumors to immune checkpoint blockade, while isogenic, wildtype tumors are resistant. Our findings describe a novel role of HuR in facilitating tumor immune suppression in the PDAC TME by inhibiting T cell infiltration and function, and implicate HuR inhibition as a potential therapeutic combination with immunotherapy.