Gut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma

  • Qianfei Zhang
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Chi Ma
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Yi Duan
    2Department of Medicine, University of California, San Diego, La Jolla, California.
  • Bernd Heinrich
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Umberto Rosato
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Laurence P. Diggs
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Lichun Ma
    4Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Soumen Roy
    5Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Qiong Fu
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Zachary J. Brown
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Simon Wabitsch
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Vishal Thovarai
    5Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Jianyang Fu
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Dechun Feng
    6Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
  • Benjamin Ruf
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Linda L. Cui
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Varun Subramanyam
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Karen M. Frank
    7Microbiology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland.
  • Sophie Wang
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • David E. Kleiner
    8Laboratory of Pathology, NIH, Bethesda, Maryland.
  • Thomas Ritz
    9Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Christian Rupp
    11Department of Gastroenterology, University Hospital of Heidelberg, Heidelberg, Germany.
  • Bin Gao
    6Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
  • Thomas Longerich
    9Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Alexander Kroemer
    12MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia.
  • Xin Wei Wang
    4Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Mathuros Ruchirawat
    14Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, Thailand.
  • Firouzeh Korangy
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Bernd Schnabl
    2Department of Medicine, University of California, San Diego, La Jolla, California.
  • Giorgio Trinchieri
    5Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Tim F. Greten
    1Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

抄録

<jats:title>Abstract</jats:title><jats:sec><jats:title /><jats:p>Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders; however, its effect on antitumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects antitumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis, two known risk factors for cholangiocarcinoma which promote tumor development in mice, caused an accumulation of CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). A decrease in gut barrier function observed in mice with PSC and colitis allowed gut-derived bacteria and lipopolysaccharide to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2+ PMN-MDSCs. In contrast, neomycin treatment blocked CXCL1 expression and PMN-MDSC accumulation and inhibited tumor growth even in the absence of liver disease or colitis. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSCs to promote liver cancer.</jats:p></jats:sec><jats:sec><jats:title>Significance:</jats:title><jats:p>MDSCs have been shown to be induced by tumors and suppress antitumor immunity. Here we show that the gut microbiome can control accumulation of MDSCs in the liver in the context of a benign liver disease or colitis.</jats:p><jats:p>See related commentary by Chagani and Kwong, p. 1014.</jats:p><jats:p>This article is highlighted in the In This Issue feature, p. 995</jats:p></jats:sec>

収録刊行物

  • Cancer Discovery

    Cancer Discovery 11 (5), 1248-1267, 2020-12-15

    American Association for Cancer Research (AACR)

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