Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer
- Carlo Schneider1,
- Andreas Teufel2,
- Tetyana Yevsa3,4,
- Frank Staib2,
- Anja Hohmeyer3,4,
- Gudrun Walenda1,
- Henning W Zimmermann1,
- Mihael Vucur1,
- Sebastian Huss5,
- Nikolaus Gassler6,
- Hermann E Wasmuth1,
- Sergio A Lira7,
- Lars Zender3,4,
- Tom Luedde1,
- Christian Trautwein1,
- Frank Tacke1
- 1Department of Medicine III, University Hospital, RWTH-Aachen, Aachen, Germany
- 2Department of Medicine I, University of Mainz, Mainz, Germany
- 3Helmholtz Centre for Infection Research, Braunschweig, Germany
- 4Department of Gastroenterology, Hepatology & Endocrinology, Medical School Hannover, Hannover, Germany
- 5Institute of Pathology, University of Bonn, Bonn, Germany
- 6Institute of Pathology, University Hospital, RWTH-Aachen, Aachen, Germany
- 7Immunology Institute, Mount Sinai Medical Centre, New York, New York, USA
- Correspondence to Professor Frank Tacke, Department of Medicine III, University Hospital Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany;
Contributors CS, GW, TY and MV performed mouse experiments and analysed the results; FS and AT performed bioinformatics analyses from gene array datasets; AH provided the OVA-expressing vectors; SH and NG performed conventional histology, immunohistochemistry and analysed results; SAL provided knockout mice; HWZ, HEW and LZ helped in data interpretation and provided important intellectual content; CS, TL, CT and FT designed the study, analysed data and wrote the manuscript.
- Revised 22 December 2011
- Accepted 23 December 2011
- Published Online First 20 January 2012
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.
Design 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.
- adaptive immunity
- acute hepatitis
- antibody targeted therapy
- autoimmune liver disease
- gastric cancer
- acute liver failure
- cancer genetics
- hepatocellular carcinoma
- immune-mediated liver damage
- immunology in hepatology
- liver immunology
- molecular biology
- molecular carcinogenesis
- cell death
- chronic liver disease
- liver cirrhosis
- molecular genetics
- linkage analysis
- hepatitis C
Funding This work was supported by the German Research Foundation (DFG Ta434/2-1 to F.T., DFG SFB/TRR 57), by the Start-program and Interdisciplinary Centre for Clinical Research (IZKF) at RWTH-Aachen University.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All primary data are available upon request. SAL can be contacted about the D6-deficient mice, AH and LZ about the OVA-expressing plasmid.