Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer

Dai Liu, Guangfu Li, Diego M. Avella, Eric T. Kimchi, Jussuf T. Kaifi, Mark P. Rubinstein, E. Ramsay Camp, Don C. Rockey, Todd D. Schell, Kevin F. Staveley-O'Carroll

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11 Scopus citations

Abstract

Successful development of immunotherapeutic strategies for hepatocellular cancer (HCC) has been impeded by limited understanding of tumor-induced profound tolerance and lack of a clinically faithful HCC model. Recently, we developed a novel model that recapitulates typical features of human HCC. Using this clinically relevant model, we demonstrate that tumor growth impairs host immunity and causes a profound exhaustion of tumor antigen-specific (TAS) CD8+ T cells. Increase in frequency and suppressive function of regulatory T cells (Tregs) is critically involved in this tumor-induced immune dysfunction. We further demonstrate that sunitinib suppresses Tregs and prevents tumor-induced immune tolerance, allowing TAS immunization to activate endogenous CD8+ T cells. As a result, this combinational strategy delays tumor growth. Importantly, the additional integration of exogenous naïve TAS CD8+ T cells by adoptive cell transfer (ACT) leads to the elimination of the established tumors without recurrence and promotes long-term survival of the treated mice. Mechanistically, sunitinib treatment primes the antitumor immune response by significantly decreasing Treg frequency, reducing TGF-β and IL-10 production by Tregs, and also protecting TAS CD8+ T cells from tumor-induced deletion in the setting of HCC. Taken together, sunitinib quantitatively and qualitatively modifies Tregs to overcome tumor-induced immune deficiency, suggesting the potential of sunitinib as a therapeutic immune activator for HCC control.

Original languageEnglish (US)
JournalOncoImmunology
DOIs
StateAccepted/In press - Sep 20 2017

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology

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    Liu, D., Li, G., Avella, D. M., Kimchi, E. T., Kaifi, J. T., Rubinstein, M. P., Camp, E. R., Rockey, D. C., Schell, T. D., & Staveley-O'Carroll, K. F. (Accepted/In press). Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer. OncoImmunology. https://doi.org/10.1080/2162402X.2017.1372079