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.
View: Text | PDF
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

×

Figure 2

Immunity to the cancer-driving oncogene following virus-induced activation.

Options: View larger image (or click on image) Download as PowerPoint
Immunity to the cancer-driving oncogene following virus-induced activati...
(A) The amount of TAg-specific IgG antibodies was determined in serum obtained from B6 (n = 4) and LoxP-TAg mice (Tg) 3 (n = 14) and 20 weeks (n = 7) after i.v. injection of Ad.Cre (1 × 109 PFUs). Bars indicate mean values. As controls, LoxP-TAg mice were i.v. injected with 1 × 109 PFUs of Ad.Luc (n = 4). LoxP-TAg mice analyzed 20 weeks after Ad.Cre injection had macroscopically visible tumors (see Figure 1, B and D). (B) LoxP-TAg mice develop TAg-specific antibodies of IgG1, IgG2a, and IgG2b isotypes upon Ad.Cre-mediated TAg activation. Amounts of TAg-specific IgG1, IgG2a, IgG2b, and IgG3 were determined in serum obtained from individual mice 3 and 20 weeks after Ad.Cre application. IgG3 was not detectable in any serum sample (not shown). Each number represents an individual mouse. LTB, large tumor bearing. (C) CD4+ T cell–deficient (Cd4–/– × LoxP-TAg; n = 6) and CD8+ T cell–deficient mice (Cd8–/– × LoxP-TAg; n = 4) received 1 × 109 PFUs of Ad.Cre and were monitored for HCC development. Ad.Cre-treated T cell–competent LoxP-TAg mice (WT × LoxP-TAg; n = 5) served as controls. (D) Ad.Cre-treated Rag2–/–cg–/– × LoxP-TAg mice (n = 7) were monitored for HCC development. LoxP-TAg mice (n = 6) served as control. (E) TAg-tolerant Vil-Cre × LoxP-TAg mice (n = 6) were injected with 1 × 109 PFUs of Ad.Cre and monitored for HCC development. LoxP-TAg mice (n = 9) served as controls. (C–E) Time after adenovirus infection is given.