Combination of Sunitinib-targeted Therapy with T Cell Immunotherapy for Eradicating Established Liver Tumors

Résumé du livre

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its incidence has been increasing in the US over the past decades. The high rate of mortality, recurrence and the limited efficacy of current therapies highlight the urgent need for new therapeutic approaches. HCC is known to express tumor-specific antigens which are potential targets for immunotherapy. However, tumor-induced immunotolerance thwarts the effective immune responses and challenges the development of immune-based therapies. The underlying mechanisms of HCC-induced immunotolerance have been difficult to study in the absence of realistic animal models. Recently, we established a unique HCC murine model in our laboratory, in which hepatocytes reproducibly develop into discrete foci of HCC concomitantly with progressive hepatic fibrosis in immunocompetent mice. This model approximates the process that commonly occurs in human, resulting in tumors that are histologically similar to human HCC. Our unique murine model provides an ideal platform to elucidate the cellular and molecular mechanisms of tumor antigen-specific immunotolerance associated with HCC. Using this model, we investigate the use of the FDA-approved chemotherapeutic agent, sunitinib, in modulation of tumor antigen-specific immunotolerance as well as to determine its efficacy in combination with T-cell based immunotherapy for established HCC. In this study, we will test our central hypothesis that sunitinib treatment inhibits tumor-induced immunotolerance in HCC tumorbearing mice by modulating regulatory T cells, which allows the activation of effector CD8 T cells. Targeting these mechanisms will improve the design of novel therapies for advanced HCC.