title: NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis.
abstract: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.
authors.affiliation: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Ma
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Aparna H
authors.initials: AH
authors.lastname: Kesarwala
authors.affiliation: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eggert
authors.affiliation: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: José
authors.initials: J
authors.lastname: Medina-Echeverz
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.affiliation: Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Stroncek
authors.affiliation: Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Terabe
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.affiliation: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: ElGindi
authors.affiliation: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Miaojun
authors.initials: M
authors.lastname: Han
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Thornton
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Surgical Pathology, University and University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Michèle
authors.initials: M
authors.lastname: Egger
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Luo
authors.affiliation: Division of Oncology, Department of Medicine and Pathology, Stanford University, California 94305, USA.
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland 21702, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McVicar
authors.affiliation: Institute of Surgical Pathology, University and University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich 81675, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D063646:Carcinogenesis / Q000276:immunology / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002794:Choline / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D016259:Genes, myc; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019787:Linoleic Acid / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D019787:Linoleic Acid; D008715:Methionine; D002794:Choline