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| Item Type: | Article |
|---|---|
| Title: | Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance |
| Creators Name: | Willimsky, G., Schmidt, K., Loddenkemper, C., Gellermann, J. and Blankenstein, T. |
| 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. |
| 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 |
| Source: | Journal of Clinical Investigation |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 123 |
| Number: | 3 |
| Page Range: | 1032-1043 |
| Date: | 1 March 2013 |
| Official Publication: | https://doi.org/10.1172/JCI64742 |
| PubMed: | View item in PubMed |
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