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

Diego M. Avella, Guangfu Li, Todd Schell, Dai Liu, Samuel Shao Min Zhang, Xi Lou, Arthur Berg, Eric T. Kimchi, Hephzibah Rani S. Tagaram, Qing Yang, Serene Shereef, Luis S. Garcia, Mark Kester, Harriet C. Isom, C. Bart Rountree, Kevin F. Staveley-O'Carroll

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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.

Original languageEnglish (US)
Pages (from-to)141-152
Number of pages12
JournalHepatology
Volume55
Issue number1
DOIs
StatePublished - Jan 1 2012

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Hepatocellular Carcinoma
Neoplasm Antigens
T-Lymphocytes
Adoptive Transfer
Neoplasms
Hepatocytes
Therapeutics
Polyomavirus Transforming Antigens
Recurrence
Liver
Viral Tumor Antigens
Receptor Protein-Tyrosine Kinases
Growth
Inbred C57BL Mouse
Transgenic Mice
sunitinib
Antigens
Mortality
Incidence

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Avella, D. M., Li, G., Schell, T., Liu, D., Zhang, S. S. M., Lou, X., ... Staveley-O'Carroll, K. F. (2012). Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model. Hepatology, 55(1), 141-152. https://doi.org/10.1002/hep.24652
Avella, Diego M. ; Li, Guangfu ; Schell, Todd ; Liu, Dai ; Zhang, Samuel Shao Min ; Lou, Xi ; Berg, Arthur ; Kimchi, Eric T. ; Tagaram, Hephzibah Rani S. ; Yang, Qing ; Shereef, Serene ; Garcia, Luis S. ; Kester, Mark ; Isom, Harriet C. ; Rountree, C. Bart ; Staveley-O'Carroll, Kevin F. / Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model. In: Hepatology. 2012 ; Vol. 55, No. 1. pp. 141-152.
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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.",
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Avella, DM, Li, G, Schell, T, Liu, D, Zhang, SSM, Lou, X, Berg, A, Kimchi, ET, Tagaram, HRS, Yang, Q, Shereef, S, Garcia, LS, Kester, M, Isom, HC, Rountree, CB & Staveley-O'Carroll, KF 2012, 'Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model', Hepatology, vol. 55, no. 1, pp. 141-152. https://doi.org/10.1002/hep.24652

Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model. / Avella, Diego M.; Li, Guangfu; Schell, Todd; Liu, Dai; Zhang, Samuel Shao Min; Lou, Xi; Berg, Arthur; Kimchi, Eric T.; Tagaram, Hephzibah Rani S.; Yang, Qing; Shereef, Serene; Garcia, Luis S.; Kester, Mark; Isom, Harriet C.; Rountree, C. Bart; Staveley-O'Carroll, Kevin F.

In: Hepatology, Vol. 55, No. 1, 01.01.2012, p. 141-152.

Research output: Contribution to journalArticle

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T1 - Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model

AU - Avella, Diego M.

AU - Li, Guangfu

AU - Schell, Todd

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AU - Zhang, Samuel Shao Min

AU - Lou, Xi

AU - Berg, Arthur

AU - Kimchi, Eric T.

AU - Tagaram, Hephzibah Rani S.

AU - Yang, Qing

AU - Shereef, Serene

AU - Garcia, Luis S.

AU - Kester, Mark

AU - Isom, Harriet C.

AU - Rountree, C. Bart

AU - Staveley-O'Carroll, Kevin F.

PY - 2012/1/1

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N2 - 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.

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