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Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance

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Official URL:https://doi.org/10.1172/JCI64742
PubMed:View item in PubMed
Creators Name:Willimsky, G. and Schmidt, K. and Loddenkemper, C. and Gellermann, J. and Blankenstein, T.
Journal Title:Journal of Clinical Investigation
Journal Abbreviation:J Clin Invest
Volume:123
Number:3
Page Range:1032-1043
Date:1 March 2013
Keywords:Adenoviridae, Animal Disease Models, CD274 Antigens, CD8-Positive T-Lymphocytes, Cytotoxic T-Lymphocytes, Experimental Liver Neoplasms, Hepatocellular Carcinoma, Immune Tolerance, Neoplasm Transplantation, Polyomavirus Transforming Antigens, Programmed Cell Death 1 Receptor, Transgenic Mice, Tumor Burden, Tumor Cell Line, Tumor Escape, Tumor Virus Infections, Viral Antibodies, Animals, Mice
Abstract:T cell surveillance is often effective against virus-associated tumors because of their high immunogenicity. It is not clear why surveillance occasionally fails, particularly against hepatitis B virus- or hepatitis C virus-associated hepatocellular carcinoma (HCC). We established a transgenic murine model of virus-induced HCC by hepatocyte-specific adenovirus-induced activation of the oncogenic SV40 large T antigen (TAg). Adenovirus infection induced cytotoxic T lymphocytes (CTLs) targeted against the virus and TAg, leading to clearance of the infected cells. Despite the presence of functional, antigen-specific T cells, a few virus-infected cells escaped immune clearance and progressed to HCC. These cells expressed TAg at levels similar to HCC isolated from neonatal TAg-tolerant mice, suggesting that CTL clearance does not select for cells with low immunogenicity. Virus-infected mice revealed significantly greater T cell infiltration in early-stage HCC compared with that in late-stage HCC, demonstrating progressive local immune suppression through inefficient T cell infiltration. Programmed cell death protein-1 (PD-1) and its ligand PD-L1 were expressed in all TAg-specific CD8+ T cells and HCC, respectively, which contributed to local tumor-antigen-specific tolerance. Thus, we have developed a model of virus-induced HCC that may allow for a better understanding of human HCC.
ISSN:0021-9738
Publisher:American Society for Clinical Investigation (U.S.A.)
Item Type:Article

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