Abstract A043: The tumor-intrinsic RNA binding protein HuR is essential for anti-tumor immunity in PDAC

Abstract

Abstract Immunotherapies have shown limited effectiveness in pancreatic ductal adenocarcinoma (PDAC), despite successes in many other cancers. The RNA-binding protein HuR is known to play a critical role in the oncogenesis of PDAC through regulating key mRNA transcripts. Our lab has showed that tumor-intrinsic HuR is overexpressed in PDAC and regulates the tumor microenvironment composition and alters multiple tumor cytokine release. Thus, we hypothesized that HuR plays a role in immune evasion of PDAC. We disrupted the locus encoding HuR (Elavl1), using CRISPR Cas9 in Kras-p53 mutant-driven (KPC) murine PDAC to assess its function in tumor immune evasion. Here, we report that HuR, a known pro-survival factor for PDAC, has a role in tumor immune evasion by suppressing T cell infiltration and T cell activation. Specifically, HuR-knockout (KO) KPC tumors grew slower compared to KPC wildtype (WT) tumors in an orthotopically implantation model (p-value<0.0001), even though they grew at the same rate in vitro (in a non-compromised environment). Accordingly, HuR-KO tumors had more T cell infiltration and activated T cells comparing to HuR-WT tumors (p-value=0.0047). Furthermore, T cell depletion partially rescued the size of HuR-KO tumors. Collectively, these data support the hypothesis that HuR suppresses T cell activation and prevents T cells from infiltrating the PDAC microenvironment, which therefore leads to PDAC immune evasion. Ongoing experiments will transduce KPC cell lines with ovalbumin (OVA) antigen, which will selectively active CD8+ OT-I T cells through their transgenic TCR, to measure the ability of KPC HuR-WT or HuR-KO OVA cells in directly activating CD8+ OT-I T cells. We will also rescue HuR in HuR-KO cells to validate HuR’s role in immune evasion. These findings support the concept that HuR plays an important pro-survival role of PDAC in vivo, and that targeting strategies against HuR being developed (e.g., siHuR nanotherapies and small molecule inhibitors) could potentially enhance PDAC sensitivity to immune-based anti-cancer therapies such as checkpoint blockade and T cell transfer. Citation Format: Yifei Guo, Jennifer M. Finan, Madeline D. Hedberg, Jonathan R. Brody, Robert Eil. The tumor-intrinsic RNA binding protein HuR is essential for anti-tumor immunity in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A043.