Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model

Hepatology. 2012 Jan;55(1):141-52. doi: 10.1002/hep.24652.


The high rate of mortality and frequent incidence of recurrence associated with hepatocellular carcinoma (HCC) reveal the need for new therapeutic approaches. In this study we evaluated the efficacy of a novel chemoimmunotherapeutic strategy to control HCC and investigated the underlying mechanism that increased the antitumor immune response. We developed a novel orthotopic mouse model of HCC through seeding of tumorigenic hepatocytes from SV40 T antigen (Tag) transgenic MTD2 mice into the livers of syngeneic C57BL/6 mice. These MTD2-derived hepatocytes form Tag-expressing HCC tumors specifically within the liver. This approach provides a platform to test therapeutic strategies and antigen-specific immune-directed therapy in an immunocompetent murine model. Using this model we tested the efficacy of a combination of oral sunitinib, a small molecule multitargeted receptor tyrosine kinase (RTK) inhibitor, and adoptive transfer of tumor antigen-specific CD8(+) T cells to eliminate HCC. Sunitinib treatment alone promoted a transient reduction in tumor size. Sunitinib treatment combined with adoptive transfer of tumor antigen-specific CD8(+) T cells led to elimination of established tumors without recurrence. In vitro studies revealed that HCC growth was inhibited through suppression of STAT3 signaling. In addition, sunitinib treatment of tumor-bearing mice was associated with suppression of STAT3 and a block in T-cell tolerance.

Conclusion: These findings indicate that sunitinib inhibits HCC tumor growth directly through the STAT3 pathway and prevents tumor antigen-specific CD8(+) T-cell tolerance, thus defining a synergistic chemoimmunotherapeutic approach for HCC.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Adoptive Transfer / methods*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / transplantation
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Combined Modality Therapy
  • Disease Models, Animal
  • Hep G2 Cells
  • Hepatocytes / immunology
  • Hepatocytes / transplantation
  • Humans
  • Immune Tolerance / immunology
  • Immunocompetence / immunology
  • Indoles / pharmacology*
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pyrroles / pharmacology*
  • STAT3 Transcription Factor / immunology
  • STAT3 Transcription Factor / metabolism
  • Sunitinib


  • Antineoplastic Agents
  • Indoles
  • Pyrroles
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Sunitinib