Abstract 5357: 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 having success in other cancers. The RNA-binding protein HuR is known to play a critical role in the oncogenesis of PDAC by regulating key mRNA transcripts. Our lab has shown that tumor-intrinsic HuR is overexpressed in PDAC and regulates the tumor microenvironment composition, altering multiple tumor cytokines to 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 implanted model (p-value < 0.0001), even though human PDAC cell lines with HuR-WT and HuR-KO grew at the same rate in NRG mice (in an immune-compromised environment). Accordingly, HuR-KO tumors had more T cell infiltration and activated T cells compared to HuR-WT tumors (p-value = 0.0047). Importantly, T cell depletion (both CD4+ and CD8+) partially rescued the size of HuR-KO tumors. Next, we rescued the expression of HuR in the HuR-KO cell line, and the re-expression partially rescued the tumor size in vivo. This observation validates a HuR-mediated dependent mechanism. Collectively, these data support the hypothesis that HuR suppresses T cell activation and prevents T cells from infiltrating into the PDAC microenvironment, leading to PDAC immune evasion. Ongoing experiments will transduce KPC cell lines with ovalbumin (OVA) antigen, which will selectively activate 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 investigate HuR's impact on immune cells' cytokine release and how that will impact the cytotoxicity of T cells. These findings support the ongoing concept that HuR plays an important pro-survival role in PDAC in vivo, and targeting strategies against HuR being developed (e.g., siHuR nano-therapies 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, Alexandra Q. Bartlett, 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 American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5357.