{
  "abstract": "Background The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by limited infiltration of tumor-specific effector T cells, contributing to resistance to immunotherapy. 1 While the abundance of fibrotic stroma, suppressive myeloid populations, and nutrient deprivation have been extensively studied as mediators of immune evasion in PDAC, the role of post-transcriptional gene regulation in tumor-immune crosstalk remains relatively unexplored. Tumor-intrinsic HuR has been shown to remodel the PDAC TME by promoting matrix deposition.2 Thus, we hypothesized that tumor-intrinsic HuR might also play role in remodeling the immune population in PDAC TME.Methods We analyzed patient sequencing databases and tumor microarray staining to identify correlations between HuR expression and T cell infiltration in PDAC tumors. Using CRISPR/Cas9, we generated HuR-proficient (WT) and HuR-deficient (KO) cells from a established Kras-p53-Cre (KPC) mutant-driven murine PDAC cell lines. These cells were orthotopically implanted into the pancreas of immunocompetent C57BL/6 mice, and tumor growth was monitored. Immune cell infiltration and activation status in the implanted tumors were analyzed via flow cytometry and multiplex immunohistochemistry. RNA sequencing, HuR-binding RNA immunoprecipitation, and pathway inhibition studies were performed to identify HuR-mediated mechanisms of immune suppression in tumors.Results The RNA-binding protein, HuR ( ELAVL1), is highly enriched in PDAC and negatively correlates with T cell infiltration. In a Kras-p53-Cre (KPC) orthotopic model of PDAC, we found that genetic disruption of HuR impaired tumor growth in the immunocompetent setting. Importantly, comprehensive spatial profiling of the PDAC TME revealed that genetic disruption of HuR in PDAC enhanced both T cell number and activation and diminished myeloid phenotypes. Mechanistically, HuR mediated the stabilization of mTOR pathway transcripts, while inhibition of mTOR activity in HuR-proficient PDAC rescued the impaired function of local T cells. The impact of HuR-mediated immune evasion was translationally relevant, as we found that HuR depletion sensitized PDAC tumors to immune checkpoint blockade, while isogenic, wildtype tumors were resistant.Conclusions For the first time, this study identified a novel mechanism that post-transcriptional regulator HuR supports pancreatic tumor growth by promoting immune evasion. We show that HuR facilitates immune evasion in PDAC by inhibiting T cell infiltration and effector function, implicating targeting HuR as a promising therapeutic strategy in combination with immunotherapy.References Ullman NA, Burchard PR, Dunne RF, Linehan DC. Immunologic strategies in pancreatic cancer: making cold tumors hot . J Clin Oncol. 2022;40(24):2789–2805. doi:10.1200/JCO.21.02616.McCarthy GA, Di Niro R, Finan JM, et al. Deletion of the mRNA stability factor ELAVL1 (HuR) in pancreatic cancer cells disrupts the tumor microenvironment integrity. NAR Cancer. 2023;5(2):zcad016. doi:10.1093/narcan/zcad016.",
  "authors": [
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Yifei Guo"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Jennifer M Finan"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Alexandra Q Bartlett"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Shamilene Sivagnanam"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Katie E Blise"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Nell Kirchberger"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Konjit Betre"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Vidhi Shah"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Koei Chin"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Grace A McCarthy"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Kevin MacPherson"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Canping Chen"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Aaron J Grossberg"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Zheng Xia"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Lisa M Coussens"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Rosalie C Sears"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Jonathan R Brody"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Robert Eil"
    }
  ],
  "title": "1250 Post-transcriptional regulator HuR promotes immune evasion in pancreatic ductal adenocarcinoma",
  "uid": "e24040ba-e03c-55c6-a3ee-de7662acb852"
}