Tumor-Mediated Suppression of Dendritic Cell Vaccines

摘要

The unique ability of dendritic cells to potently stimulate 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 DC functions. One of the best characterized of these factors is Transforming growth factor- beta (TGF-beta), a multifunctional cytokime 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. In this study we show that TGF-beta suppression of DC vaccines can be mitigated by inhibiting TCF-B gene expression in tumor cells and by neutralization of secreted TGF-beta with specific antibody. We demonstrate that a novel small molecule TGF-beta type 1 receptor kinase inhibitor abrogates tumor-derived TGF- beta-mediated signaling and epithelial-mesenchymal transition characteristic of a more invasive phenotype. The inhibitor enhanced the effectiveness of DC vaccines in controlling the growth of established 4T1 tumors. Taken together, our studies demonstrate the usefulness of eliminating immunosuppressive tumor- derived products in order to improve the effectiveness of dendritic cell-based anti-cancer vaccines.