{
  "abstract": "Background Atezolizumab plus bevacizumab (Atez/Bev) has become the first-line therapy for unresectable hepatocellular carcinoma (HCC). However, reliable biomarkers to predict therapeutic response remain lacking.Methods We conducted a high-throughput plasma proteomic screen using the Olink proximity extension assay to identify predictive biomarkers in 78 patients with unresectable HCC treated with Atez/Bev. Validation was performed in an independent cohort of 89 patients. Tumorous expression of the lead candidate, carbonic anhydrase 9 (CA9), was examined using transcriptomic and single-cell analyses. Functional studies were performed in a syngeneic mouse model using Car9-overexpressing hepatoma cells, treated with anti-programmed death-ligand 1/vascular endothelial growth factor antibodies, with or without a CA9 inhibitor.Results High plasma CA9 levels were significantly associated with poor objective response rate, disease control rate, progression-free survival, and overall survival in both discovery and validation cohorts. Multivariable analysis confirmed CA9 as an independent predictor of treatment resistance and poor outcomes. Tumorous CA9 expression correlated strongly with circulating CA9 and was restricted to malignant cells. In vivo, tumors overexpressing Car9 showed resistance to Atez/Bev therapy, characterized by reduced CD8+T cell infiltration, suppressed cytotoxic gene expression, enrichment of M2-like macrophages, and pro-angiogenic signaling. The addition of a CA9 inhibitor reversed resistance and restored antitumor efficacy of Atez/Bev in this model.Conclusions Tumor-derived circulating CA9 is a predictive biomarker and functional driver of resistance to Atez/Bev therapy in HCC. Targeting CA9 may enhance therapeutic response.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"
      ],
      "name": "Yu Sato"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"
      ],
      "name": "Takahiro Kodama"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"
      ],
      "name": "Kazuki Maesaka"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"
      ],
      "name": "Machiko Kai"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"
      ],
      "name": "Kazuhiro Murai"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"
      ],
      "name": "Yuki Tahata"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"
      ],
      "name": "Yoshinobu Saito"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan"
      ],
      "name": "Tasuku Nakabori"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan"
      ],
      "name": "Kazuyoshi Ohkawa"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan"
      ],
      "name": "Satoshi Tanaka"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan"
      ],
      "name": "Ryotaro Sakamori"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Osaka Police Hospital, Osaka, Japan"
      ],
      "name": "Masanori Miyazaki"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Ikeda Municipal Hospital, Ikeda, Japan"
      ],
      "name": "Kunimaro Furuta"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Ikeda Municipal Hospital, Ikeda, Japan"
      ],
      "name": "Hisashi Ishida"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Japan"
      ],
      "name": "Kengo Matsumoto"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Osaka General Medical Center, Osaka, Japan"
      ],
      "name": "Seiichi Tawara"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Osaka General Medical Center, Osaka, Japan"
      ],
      "name": "Takayuki Yakushijin"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Kansai Rosai Hospital, Amagasaki, Japan"
      ],
      "name": "Yasutoshi Nozaki"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Osaka Rosai Hospital, Sakai, Japan"
      ],
      "name": "Atsushi Hosui"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan"
      ],
      "name": "Akira Nishio"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan"
      ],
      "name": "Nobuyuki Tatsumi"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Kaizuka City Hospital, Kaizuka, Japan"
      ],
      "name": "Naruyasu Kakita"
    },
    {
      "affiliations": [
        "Department of Oncology, University of Ulsan College of Medicine, Songpa-gu, Korea (the Republic of)"
      ],
      "name": "Changhoon Yoo"
    },
    {
      "affiliations": [
        "Department of Gastroenterological Surgery I, Hokkaido University, Sapporo, Japan"
      ],
      "name": "Moto Fukai"
    },
    {
      "affiliations": [
        "Department of Gastroenterological Surgery I, Hokkaido University, Sapporo, Japan"
      ],
      "name": "Akinobu Taketomi"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"
      ],
      "name": "Hayato Hikita"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"
      ],
      "name": "Tomohide Tatsumi"
    },
    {
      "affiliations": [
        "Kansai Rosai Hospital, Amagasaki, Japan"
      ],
      "name": "Tetsuo Takehara"
    }
  ],
  "title": "Carbonic anhydrase 9 as a circulating biomarker and therapeutic target in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab",
  "uid": "dac5d02c-1d62-5ba5-98b1-146d8432e03b"
}