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 5

Ad.Cre-induced HCCs in LoxP-TAg mice cause antigen-specific local tolerance.

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Ad.Cre-induced HCCs in LoxP-TAg mice cause antigen-specific local tolera...
(A) HCC tissues were stained for CD3, F4/80, and FoxP3 expression. Arrows indicate a small TAg+ lesion (also depicted in Figure 1D). One representative out of three experiments per time point is shown. (B) 1 × 106 TAg+ 16.113gl cells were injected i.h. into Rag2–/– and HCC-bearing LoxP-TAg mice, and 7–12 weeks later liver tissues were stained for TAg and HepPar1. HepPar1-negative areas indicate 16.113 tumors (asterisks). Note that tumors grew in both groups of mice. Scale bar: 100 μm (A and B). (C) Selection of antigen-loss variants of 16.113gl cells in LoxP-TAg × Alb-Cre but not Rag2–/– mice. LoxP-TAg × Alb-Cre (6 weeks), young LoxP-TAg (8 weeks), large tumor-bearing LoxP-TAg (95 weeks), and Rag2–/– mice (8–12 weeks) injected s.c. with 1 × 107 16113gl cells were analyzed by BL imaging and tumor growth. Nontreated mice injected with luciferin served as controls (–; bkg ctrl). Images are representative for 2 experiments. (D) Tumor growth and Fluc signals of mice shown in C. Data shown are combined from 2 experiments; error bars represent SEM. Age and number of mice are shown in parenthesis. (E) Loss of BL signal of i.h. injected 16.113gl cells in HCC-bearing LoxP-TAg mice, but not in Rag2–/– mice, 2–6 months after Ad.Cre infection, as detected by BL imaging. Representative Rag2–/– (s.c., n = 2; i.h., n = 4) and HCC-bearing mice (i.h., n = 14) 7 weeks after 16.113gl cell injection are shown. See also Supplemental Figure 8.