Combination of sunitinib-targeted therapy with T cell immunotherapy for eradicating established liver tumors

Open Access
Author:
Liu, Dai
Graduate Program:
Molecular Medicine
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
June 11, 2013
Committee Members:
  • Charles H Lang, Dissertation Advisor
  • Thomas Loughran, Committee Member
  • Todd Schell, Committee Member
  • Harriet C Isom, Committee Member
  • Kevin Staveley O'carroll, Special Member
Keywords:
  • Regulatory T cells
  • Hepatocellular carcinoma
  • CD8 T cells
  • Sunitinib
  • Immunotherapy
Abstract:
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 tumor-bearing 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. In aim 1, we attempt to determine the tumor induced tolerance of antigen-specific CD8 T cells in HCC. We approach this question by investigating how tumors escape from the attention of the immune system during tumor initiation and development as well as the involvement of immune regulatory populations during tumor progression. In aim 2, we define the role of sunitinib in preventing tumor antigen-specific CD8 T cell tolerance by comparing the phenotype, function and interaction of immune cells in tumor-bearing mice with and without sunitinib treatment. We especially focus on the changes within the regulatory T cells and tumor microenvironment where limited data are available for HCC. In addition, we evaluate the therapeutic efficacy of combination strategies including antigen specific T cells transfer and immunization. We will further examine the molecular pathways involved in sunitinib-mediated immunomodulation. In this thesis study, we made the critical observation that sunitinib combined with adoptive transfer of CD8 T cells lead to durable long-term regression of established HCC tumors. The successful therapeutic effect is associated with changes in TGF-β and IL-10 as well as a reduction of regulatory T cells and activation of antigen-specific CD8 T cells. Our findings indicate that sunitinib prevents the development of an immunosuppressive state within the liver, allowing effective T cell-based immunotherapy. This study improves our knowledge regarding mechanisms of sunitinib-enhanced immunity to cancer. Our findings provide important preclinical data for translating chemo-immunotherapeutic approaches into practical strategies to improve clinical outcomes.