The unique ability of dendritic cells to potently stimulate naive T lymphocytes has made them prime candidates for cancer immunotherapy. In several rodent models, vaccination with antigen-pulsed dendritic cells confers protection against subsequent tumors. The inability of DC-based vaccines to cause significant regression of existing tumors has been attributed, in part, to the negative immunomodulatory effects of the tumor microenvironment. A number of tumor-derived products have been suggested to promote tumor establishment and progression by interfering with 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. In tumor biopsies from melanoma, breast and lung cancer patients, TGF-beta immunostaining has been directly correlated with metastasis, disease recurrence and mortality. TGF-beta specifically interferes with DC maturation, chemotaxis, antigen recognition and T cell activation. These findings strongly suggest that strategies that increase the resistance of DCs to TGF-beta-mediated immunosuppression should enhance the effectiveness of DC-based vaccines. The hypothesis to be tested is that blockade of TGF-beta-mediated signaling in DCs will abrogate tumor-derived, TGF-beta-mediated immunosuppression leading to ore effective DC vaccines.
The Specific Aims of this study are to: 1) determine the effect of tumor-derived TGF-beta on in vivo migratory and immune stimulatory activities of DC 2) evaluate the impact of tumor-derived TGF-beta on DC vaccines. 3) block TGF-beta-mediated signal transduction in DCs in order to enhance the effectiveness of DC vaccines. 4) develop complementary approaches to improve the effectiveness of TGF-beta-resistant DC against established tumor. TGF-beta-mediated signal transduction will be abrogated by transfer of genes encoding a defective TGF-beta type II receptor or the TGF-beta inhibitory protein, Smad7 into DCs. These studies are expected to improve our understanding of the role of tumor-derived TGF-beta on DC function and lead to the development of improved methods for treating TFG-beta producing cancers.
