The ability to generate, maintain and target clinically-important anti-tumor immunity is critically dependent upon the appropriate presentation of tumor antigenic epitopes to T cells in lymphoid organs, as well as, the tumor itself. Recent evidence from a number of laboratories, including our own, suggests that vaccines may be most effective when they promote a phenomenon termed """"""""epitope spreading"""""""" which involves T cell stimulations in both the vaccine-draining lymph nodes and tumor-draining lymph nodes. Hence, both vaccine site and tumor-associated antigen presenting cells play major roles in the magnitude and effectiveness of such immune responses. The biasing of the type of DC accessed by a vaccine and the number and type of DC infiltrating the tumor lesion, one may theoretically augment """"""""epitope spreading and promote tumor regression and urable anti-tumor immunity. We have recently determined that one may mobilize predominantly lymphoid (CD 11c+/CD1lb-/CD 8a+) or myeloid (CD 11c+CD 1lb+/CD8a-) DC subsets based on the type or combination of mobilizing agents selected. Furthermore, in preliminary experiments we have determined that freshly-prepared lymphoid DC are the predominant producers of IL-12 in the mouse. These lymphoid DC when pulsed with tumor peptide antigens and injected into tumor bearing mice as a vaccine, far outperform myeloid DC in promoting anti-tumor immunity and tumor regression. In the current proposal, we will evaluate the """"""""clinical effects"""""""" of manipulating vaccine-associated and tumor-associated DC subsets on the ability of vaccines to promote efficacious """"""""tumorepitope spreading"""""""" within the CD4+ and CD8+ T cell compartments of tumor-bearing mice. This will be accomplished by application of both in vivo and ex vivo DC-Based Therapeutic Approaches.
Our Specific aims are: (1) Analyze the impact of mobilization and systemic maturation on murine DC subset numbers, phenotype, function, tissue localization, and established tumor growth; (2) Determine the clinical efficacy and mechanism of action of DC subset mobilization on the efficacy of tumor-antigen-based vaccines (peptides, proteins, irradiated tumor cells);(3) Determine the clinical efficacy and mechanism of action of ex vivo purified DC subset therapies in mice bearing tumors; (4) Evaluate the process of """"""""epitope spreading"""""""" in tumor-bearing mice that are mobilized, mobilized and vaccinated, or that receive DC based therapies.
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