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

Authors

  • Diego M. Avella,

    1. Department of Surgery, Division of Surgical Oncology, Pennsylvania State University College of Medicine, Hershey, PA
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    • *

      The first two authors contributed equally to this work.

  • Guangfu Li,

    1. Department of Surgery, Division of Surgical Oncology, Pennsylvania State University College of Medicine, Hershey, PA
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    • *

      The first two authors contributed equally to this work.

  • Todd D. Schell,

    1. Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA
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  • Dai Liu,

    1. Department of Surgery, Division of Surgical Oncology, Pennsylvania State University College of Medicine, Hershey, PA
    2. Department of Molecular Medicine, Pennsylvania State University College of Medicine, Hershey, PA
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  • Samuel Shao-Min Zhang,

    1. Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA
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  • Xi Lou,

    1. Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA
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  • Arthur Berg,

    1. Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA
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  • Eric T. Kimchi,

    1. Department of Surgery, Division of Surgical Oncology, Pennsylvania State University College of Medicine, Hershey, PA
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  • Hephzibah Rani S. Tagaram,

    1. Department of Surgery, Division of Surgical Oncology, Pennsylvania State University College of Medicine, Hershey, PA
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  • Qing Yang,

    1. Department of Surgery, Division of Surgical Oncology, Pennsylvania State University College of Medicine, Hershey, PA
    2. Department of Radiology, Pennsylvania State University College of Medicine, Hershey, PA
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  • Serene Shereef,

    1. Department of Surgery, Division of Surgical Oncology, Pennsylvania State University College of Medicine, Hershey, PA
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  • Luis S. Garcia,

    1. Department of Surgery, Division of Surgical Oncology, Pennsylvania State University College of Medicine, Hershey, PA
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  • Mark Kester,

    1. Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA
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  • Harriet C. Isom,

    1. Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA
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  • C. Bart Rountree,

    1. Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA
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  • Kevin F. Staveley-O'Carroll

    Corresponding author
    1. Department of Surgery, Division of Surgical Oncology, Pennsylvania State University College of Medicine, Hershey, PA
    2. Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA
    • 500 University Drive, H070, Pennsylvania State University, College of Medicine, Hershey, PA 17033
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    • fax: 717-531-3649


  • Potential conflict of interest: Dr. Rountree received grants from Bayer.

  • Grant support: KO8-CA-100094 (to K.F. Staveley-O'Carroll, PI) and R01-CA-025000 (to T.D. Schell, PI) from the National Institutes of Health.

Abstract

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. (HEPATOLOGY 2012;55:141–152)

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