Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance
Gerald Willimsky, … , Johanna Gellermann, Thomas Blankenstein
Gerald Willimsky, … , Johanna Gellermann, Thomas Blankenstein
Published February 1, 2013
Citation Information: J Clin Invest. 2013;123(3):1032-1043. https://doi.org/10.1172/JCI64742.
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Research Article Oncology

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

Gerald Willimsky, Karin Schmidt, Christoph Loddenkemper, Johanna Gellermann, Thomas Blankenstein

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Figure 6

Local tolerance is mediated by PD-1/PD-L1–dependent and –independent mechanisms.

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Local tolerance is mediated by PD-1/PD-L1–dependent and –independent mec...
(A) Spleen and liver cells from nontreated and HCC-bearing LoxP-TAg mice 27 weeks after Ad.Cre infection were analyzed for CD8 expression and Kb/IV tetramer binding. Representative plots (n = 3; range from 14%–31% double-positive cells) are shown. (B) CD8+ T cells as in A were analyzed for PD-1 expression and Kb/IV tetramer binding. Representative plots (n = 4; 7%–23% of Kb/IV tetramer+ CD8+ T cells expressed PD-1) are shown. (C) Hepatocytes from nontreated LoxP-TAg mice (liver), HCC line Ad.56, and 16.113 cells were stained with isotype control or anti–PD-L1 antibodies. Representative plots (n = 4) are shown. (D) HCC-bearing LoxP-TAg mice 12 weeks after Ad.Cre infection received anti–PD-L1 (red line, n = 5) or isotype control antibody (black line, n = 5) for 2 weeks, and survival was monitored. One of two experiments with comparable results is shown. (E) HCC-bearing LoxP-TAg mice 14 weeks after Ad.Cre injection (red line, n = 6) received irradiation (5 Gy) and 5 × 106 spleen cells from Ad.Cre-treated HCC-bearing LoxP-TAg mice (18 weeks after Ad.Cre injection) or were left untreated (black line, n = 5), and survival was monitored (see also Supplemental Figure 14B). (F) Irradiated HCC-bearing LoxP-TAg mice 16 weeks after Ad.Cre injection (red line, n = 11) were treated with 1 × 106 CD8+ T cells obtained from mice as in E or left untreated (black line, n = 4), and survival was monitored.