Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B

Giovanni Sitia, Roberto Aiolfi, Pietro Di Lucia, Marta Mainetti, Amleto Fiocchi, Francesca Mingozzi, Antonio Esposito, Zaverio M. Ruggeri, Francis V. Chisari, Matteo Iannacone, Luca G. Guidotti

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-associated HCC involves both viral and host factors. The latter include a functionally inefficient CD8+ T-cell response that fails to clear the infection from the liver but sustains a chronic necroinflammatory process that contributes to the development of HCC. According to this scenario, amelioration of immune-mediated chronic liver injury may prevent HCC. Because platelets facilitate immune-mediated liver injury by promoting the hepatic accumulation of virus-specific CD8+ T cells, we evaluated the long-term consequences of antiplatelet therapy in an HBV transgenicmousemodel of chronic immune-mediated necroinflammatory liver disease that progresses to HCC. Treatment with aspirin and clopidogrel during the chronic phase of the disease diminished the number of intrahepatic HBV-specific CD8+ T cells and HBV-nonspecific inflammatory cells, the severity of liver fibrosis, and the development of HCC. Anti-platelet therapy improved overall survival without causing significant side effects. In contrast, the same antiplatelet regimen had no antitumor effect when HCC was induced nonimmunologically by chronic exposure to a hepatotoxic chemical. The unprecedented observation that antiplatelet therapy inhibits or delays immune-mediated hepatocarcinogenesis suggests that platelets may be key players in the pathogenesis of HBV-associated liver cancer and supports the notion that immune-mediated necroinflammatory reactions are an important cause of hepatocellular transformation during chronic hepatitis.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number32
DOIs
Publication statusPublished - Aug 7 2012

Keywords

  • Antiplatelet drugs
  • CD8 T cells
  • Viral hepatitis

ASJC Scopus subject areas

  • General

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