{
  "abstract": "Background Renal cell carcinoma (RCC) responds to immunotherapy despite its low tumor mutational burden (TMB). Interestingly, the degree of CD8 + T cell infiltration in RCC negatively correlates with outcomes, suggesting that a deeper understanding of the tumor microenvironment may provide critical insight to improve outcomes.Methods Multi-omics approaches including flow cytometry, scRNA-seq, scTCR-seq, and CITE-seq were used to compare immune cell composition, gene expression, and cell-cell interactions among a cohort of primary breast cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, and RCC specimens. Putative tumor specificity was determined by flow cytometry following coculture with autologous tumor cells.Results Flow cytometry analysis of tumor-infiltrating lymphocytes (TILs) revealed increased exhausted CD8 + (Tex) and CD4+CD8+ T cells and decreased CD4+ T cells including regulatory T cells in RCC compared to other tumors. scRNA-seq analysis confirmed these results and highlighted Tex cells as a major population of CD8+ T cells. Biomarker analysis of tumor-reactive CD8+ T cells (4-1BB+, CD39+CD103+) as well as a gene signature indicative of neoantigen reactivity, revealed that Tex and CD4+CD8+ T cell populations contain putative tumor-reactive T cells. Tumor reactivity of CD4+CD8+ T cells was demonstrated by increased 4-1BB and OX40 expression following restimulation with autologous tumor cells.Conclusions Exhausted CD8 + and CD4+CD8+ T cells in RCC contain tumor-reactive T cells and may represent a novel cell population capable of targeting RCC, suggesting additional functional characterization of these populations is warranted. Understanding mechanisms of T cell exhaustion and its reversal also has important implications for therapeutic treatment of RCC and other TMB-low, potentially immunotherapy-refractory, tumors.Ethics Approval Signed informed consent was obtained before enrollment. The study was approved by the Providence St. Joseph Health Institutional Review Board – Oregon (IRB #06-108).",
  "authors": [
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Mahnaz Janghorban"
    },
    {
      "affiliations": [
        "The Ohio State University, Columbus, OH, USA"
      ],
      "name": "Yoshinobu Koguchi"
    },
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Noah D Simons"
    },
    {
      "affiliations": [
        "Oregon Health and Science University, Portland, OR, USA"
      ],
      "name": "Duncan C Hindmarch"
    },
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Wesley Rosales"
    },
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Venkatesh Rajamanickam"
    },
    {
      "affiliations": [
        "Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Tanisha L Christie"
    },
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "William L Miller"
    },
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Iliana L Gonzalez"
    },
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Melissa J Kasiewicz"
    },
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Lakhvir Kaur"
    },
    {
      "affiliations": [
        "Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Brendan D Curti"
    },
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Tarsem Mougdil"
    },
    {
      "affiliations": [
        "GlaxoSmithKline, Collegeville, PA, USA"
      ],
      "name": "Laura Wehr"
    },
    {
      "affiliations": [
        "GlaxoSmithKline, Collegeville, PA, USA"
      ],
      "name": "Niranjan Yanamandra"
    },
    {
      "affiliations": [
        "Deck Bio, Cambridge, MA, USA"
      ],
      "name": "Johanna K Kaufmann"
    },
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "Thomas M Duhen"
    },
    {
      "affiliations": [
        "Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA"
      ],
      "name": "William L Redmond"
    }
  ],
  "title": "832 Integrative multi-omics analysis reveals enrichment of exhausted CD8+ and CD4+CD8+ T cells in the renal cell carcinoma tumor microenvironment",
  "uid": "d4ea3c54-8642-5f26-b67a-4d0837d2073a"
}