title: Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is a typical inflammation-associated cancer, but may also provoke antitumour immune responses whose significance and underlying mechanisms are incompletely understood.
  
  
  OBJECTIVE
  To characterise immune responses in the diethylnitrosamine (DEN)-liver cancer mouse model.
  
  
  METHODS
  Tumour development and immune cell functions upon DEN treatment were compared between C57BL/6 wild-type (WT), chemokine scavenging receptor D6-deficient, B cell- (Igh6), CD4 T cell- (MHC-II) and T-/B cell-deficient (Rag1) mice. Relevance for human HCC was tested by comparing gene array results from 139 HCC tissues.
  
  
  RESULTS
  The induction of premalignant lesions after 24 weeks and of HCC-like tumours after 42 weeks by DEN in mice was accompanied by significant leucocyte infiltration in the liver and upregulation of distinct intrahepatic chemokines (CCL2, CCL5, CXCL9). Macrophages and CD8 (cytotoxic) T cells were most prominently enriched in tumour-bearing livers, similar to samples from human HCC. Myeloid-derived suppressor cells (MDSC) increased in extrahepatic compartments of DEN-treated mice (bone marrow, spleen). The contribution of immune cell subsets for DEN-induced hepatocarcinogenesis was functionally dissected. In D6(-/-) mice, which lack the chemokine scavenging receptor D6, hepatic macrophage infiltration was significantly increased, but tumour formation and progression did not differ from that of WT mice. In contrast, progression of hepatic tumours (numbers, diameters, tumour load) was strikingly enhanced in T-/B cell-deficient Rag1(-/-) mice upon DEN treatment. When mice deficient for B cells (Igh6(-/-), μMT) or major histocompatibility complex II were used, the data indicated that T cells prevent initial tumour formation, while B cells critically limit growth of established tumours. Accordingly, in tumour-bearing mice antibody production against liver-related model antigen was enhanced, indicating tumour-associated B cell activation. In agreement, T and B cell pathways were differentially regulated in gene array analyses from 139 human HCC tissues and significantly associated with patients' survival.
  
  
  CONCLUSIONS
  Distinct axes of the adaptive immune system, which are also prognostic in human HCC, actively suppress DEN-induced hepatocarcinogenesis by controlling tumour formation and progression.
authors.affiliation: Department of Medicine III, University Hospital, RWTH-Aachen, Aachen, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Schneider
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
authors.forename: Tetyana
authors.initials: T
authors.lastname: Yevsa
authors.forename: Frank
authors.initials: F
authors.lastname: Staib
authors.forename: Anja
authors.initials: A
authors.lastname: Hohmeyer
authors.forename: Gudrun
authors.initials: G
authors.lastname: Walenda
authors.forename: Henning W
authors.initials: HW
authors.lastname: Zimmermann
authors.forename: Mihael
authors.initials: M
authors.lastname: Vucur
authors.forename: Sebastian
authors.initials: S
authors.lastname: Huss
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.forename: Hermann E
authors.initials: HE
authors.lastname: Wasmuth
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002273:Carcinogens; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D004052:Diethylnitrosamine; D018450:Disease Progression; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002273:Carcinogens; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; D004052:Diethylnitrosamine