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 1

LoxP-TAg transgenic mice develop HCC after i.v. injection of Ad.Cre.

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LoxP-TAg transgenic mice develop HCC after i.v. injection of Ad.Cre. (A)...
(A) Cre recombinase–mediated TAg activation. (B) For induction of HCC, 8- to 12-week-old LoxP-TAg mice were injected i.v. with 1 × 109 PFUs of Ad.Cre, and HCC development was detected by MRI and palpation. Representative MR images (left) and macroscopically visible tumors of livers 10 (middle) and 20 weeks (right) after Ad.Cre injection are shown. MR image and liver photograph (middle) are from the same mouse. Arrows indicate tumor nodules. (C) LoxP-TAg mice that received Ad.Cre (red line, n = 14) and double-transgenic LoxP-TAg × Alb-Cre (DTg) mice (blue line, n = 15) were monitored for HCC development. Nontreated LoxP-TAg mice (black line; n = 10) served as control. Time after adenovirus injection is given for Ad.Cre-injected mice, and age is given for double-transgenic LoxP-TAg × Alb-Cre mice. (D) Immunohistology of liver tissue sections of LoxP-TAg mice at different time points after Ad.Cre injection as indicated. Tissues were stained with antibodies specific for TAg and Ki-67 and counterstained with hematoxylin. Scale bar: 100 μm. At least 3 mice were analyzed for each time point, and a representative staining is shown. Schematic drawings show an overview of the cumulative data of the average tumor number and progression not considering inter-mouse variability.