Abstract 4710: Sunitinib prevents tumor-induced immunotolerance in novel murine model of hepatocellular carcinoma (HCC) through modulating CD4+CD25+Foxp3+ regulatory T cells via TGF-β signaling.

The high rate of mortality, frequent incidence of recurrence, and limited benefit of current therapies for hepatocellular carcinoma underline the urgent need for new therapeutic approaches. Immunotherapy has been demonstrated to be a promising strategy for this lethal disease. However, tumor progression induced immunotolerance abrogates effective immune responses and prevents the development of successful immunotherapeutic strategies. In this study, we evaluated the role of sunitinib, a FDA approved chemotherapeutic agent, in preventing tumor-induced immunotolerance and investigated the underlying cellular and molecular mechanisms. Recently, we9ve established a novel fibrotic and orthotopic murine model of HCC through seeding of tumorigenic hepatocytes from SV40 T antigen (Tag) transgenic MTD2 mice into the livers of syngeneic C57BL/6 mice followed by carbon tetrachloride treatment. This model mimics human HCC progression and recapitulates typical histologic, biologic, and immunologic features of this disease. Using this model, we9ve demonstrated that the treatment of sunitinib, a small molecule receptor tyrosine kinase inhibitor (RTKI), restrains the tumor growth in advanced HCC. Interestingly, sunitinib treatment also induces the proliferation and differentiation of tumor antigen-specific CD8 T cells in tumor bearing mice, evidenced by significantly higher portion of CD8 T cells that produced IFN-γ and TNF-α in response to tumor antigen stimulation. Subsequent findings revealed that sunitinib treatment led to the reduction in the frequency of CD4+CD25+Foxp3+ Treg and decrease in TGF-β expression. In vitro experiments indicated that Tregs in tumor-bearing mice express higher level of TGF-β and strongly suppress the function of CD4 and CD8 T cells in a dose-dependent manner compared to that in tumor-free mice. Tregs in tumor-bearing mice treated with sunitinib exhibited reduced suppressive function compared to that in tumor-bearing mice treated with vehicle. Further, the suppressive function of Tregs from tumor-bearing mice can be partly inhibited by blocking TGF-β with anti-TGF-β antibody. In addition, we9ve demonstrated that tumor lysate drives CD4+CD25- naive T cells differentiation into CD4+CD25+Foxp3+ Tregs and this differentiation could be partially neutralized with anti-TGF-β antibody. In conclusion, our findings indicated that sunitinib treatment prevents tumor-induced immunotolerance through reducing the frequency and suppressive function of Tregs via TGF-β signaling pathway. Citation Format: Dai Liu, Guangfu Li, Eric T. Kimchi, Qing X. Yang, Todd Schell, Kevin F. Staveley-O9Carroll. Sunitinib prevents tumor-induced immunotolerance in novel murine model of hepatocellular carcinoma (HCC) through modulating CD4+CD25+Foxp3+ regulatory T cells via TGF-β signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4710. doi:10.1158/1538-7445.AM2013-4710