Tumor-Mediated Suppression of Dendritic Cell Vaccines

Abstract : The unique ability of dendritic cells to potently stimulate nave lymphocytes in an antigen-specific fashion has made them prime candidates for cancer immunotherapy. A number of tumor-derived products have been suggested to promote tumor establishment and progression by interfering with numerous DC functions required for the induction of a potent antitumor response. One of the best characterized of these tumor-derived factors is Transforming growth factor-beta (TGF-beta), a multifunctional cytokine that exerts potent suppressive effects on cells of the immune system. TGF-beta specifically interferes with DC maturation, chemotaxis, antigen recognition and T cell activation. These findings strongly suggest that a strategy that protects DCs from the harmful effects of TGF-beta should enhance the effectiveness of DC-based vaccines. The goal of this study is to protect DCs from the direct actions of tumor-derived TGF- Beta in order to improve their effectiveness as cancer vaccines. The hypothesis to be tested is that interference with TGF-Beta signal transduction in DCs will abrogate tumor-derived TGF-Beta-mediated immunosuppression leading to more effective DC vaccines. The specific aims of this study are to: 1) determine the effect of tumor-derived TGF-B on antigen presentation and in vivo migration of DCs. 2) evaluate the impact of tumor-derived TGF-Beta on DC vaccines. 3) protect DCs from TGF-Beta-mediated immunosuppression by blocking TGF-Beta signal transduction.