title: Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance.
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.
authors: Institute of Immunology, Charité Campus Benjamin Franklin, Berlin, Germany. gerald.willimsky@charite.de
authors: Gerald
authors: G
authors: Willimsky
authors: Karin
authors: K
authors: Schmidt
authors: Christoph
authors: C
authors: Loddenkemper
authors: Johanna
authors: J
authors: Gellermann
authors: Thomas
authors: T
authors: Blankenstein
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology* / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D007108:Immune Tolerance; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D047368:Tumor Burden; D019139:Tumor Escape; D014412:Tumor Virus Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology*
chemical_list: D000914:Antibodies, Viral; D000952:Antigens, Polyomavirus Transforming; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor