{
  "abstract": "Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited curative treatment options. While chimeric antigen receptor (CAR) T cells have shown some promise in solid tumors, ACC remains largely unexplored in this context. Here, we used patient-derived xenograft (PDX) models of ACC to identify immunotherapeutic targets and develop novel CAR T-cell strategies.Methods Target identification and tumor microenvironment (TME) profiling were conducted using publicly available bulk and single-cell RNA sequencing data from patients with ACC samples. Surface proteomic analysis and flow cytometry of PDXs were conducted to validate antigen candidates. CAR T cells were engineered and tested for cytotoxicity in vitro and in vivo and profiled using flow cytometry and cytokine analysis.Results We identified ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) as a shared immunotherapy target in 4/7 (57%) ACC PDXs. ENPP3-targeted CAR T-cells eradicated >85% of ENPP3 + ACC cells in vitro but showed attenuated efficacy in PDX mouse models. Restrained ENPP3 CAR T-cell activity correlated with immunosuppressive features of the TME, particularly the presence of CD206+ tumor-associated macrophages (TAMs). Co-treatment with an agent modulating CD206+ TAMs restored CAR T-cell function and improved antitumor responses in ENPP3high and ENPP3low PDX models (difference between mean tumor weights −270.1 mg±117.4; p<0.05).Conclusion ENPP3 is a novel target for CAR T-cell therapy in ACC. ENPP3 CAR T cells, when combined with CD206 modulation to overcome immune suppression within the TME, have therapeutic efficacy in ACC by mediating robust tumor growth suppression. This combinatorial strategy, which includes CAR T cells alongside therapies that recalibrate immunosuppressive CD206 + TAMs, may be a novel approach for improved immunotherapy of solid cancers beyond ACC.",
  "authors": [
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Reona Okada"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Arnulfo Mendoza"
    },
    {
      "affiliations": [
        "Advanced Biomedical Computational Science, National Cancer Institute Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA",
        "Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Darryl Nousome"
    },
    {
      "affiliations": [
        "Advanced Biomedical Computational Science, National Cancer Institute Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA",
        "Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Samarth Mathur"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Constanza Rodriguez"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Jangsuk Oh"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Katie Pendo"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Ira Phadke"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Haiying Qin"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Sitanshu S Singh"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Rosie Kaplan"
    },
    {
      "affiliations": [
        "Division of Medical Oncology, National Cancer Institute Center for Cancer Research, Bethesda, Maryland, USA"
      ],
      "name": "Jaydira del Rivero"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Mary F Wedekind"
    },
    {
      "affiliations": [
        "National Cancer Institute Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA"
      ],
      "name": "Elijah F Edmondson"
    },
    {
      "affiliations": [
        "Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Markku Miettinen"
    },
    {
      "affiliations": [
        "National Center for Advancing Translational Sciences, Bethesda, Maryland, USA"
      ],
      "name": "Kelli M Wilson"
    },
    {
      "affiliations": [
        "National Center for Advancing Translational Sciences, Bethesda, Maryland, USA"
      ],
      "name": "Shinjen Lin"
    },
    {
      "affiliations": [
        "National Center for Advancing Translational Sciences, Bethesda, Maryland, USA"
      ],
      "name": "Glenn Y Gomba"
    },
    {
      "affiliations": [
        "National Center for Advancing Translational Sciences, Bethesda, Maryland, USA"
      ],
      "name": "David O Holland"
    },
    {
      "affiliations": [
        "National Cancer Institute Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA",
        "NCI, Frederick, Maryland, USA"
      ],
      "name": "Sudipto Das"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Udo Rudloff"
    },
    {
      "affiliations": [
        "National Cancer Institute Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA"
      ],
      "name": "Thorkell Andresson"
    },
    {
      "affiliations": [
        "National Center for Advancing Translational Sciences, Bethesda, Maryland, USA"
      ],
      "name": "Ken Chih-Chien Cheng"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Xiyuan Zhang"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Karlyne M Reilly"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Brigitte Widemann"
    },
    {
      "affiliations": [
        "Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Rosa Nguyen"
    }
  ],
  "title": "ENPP3 CAR T cells combined with CD206 modulation suppress adrenocortical carcinoma",
  "uid": "21044d76-8dfd-5778-9a6e-f589772bc937"
}