A number of studies have demonstrated defective immunity in cancer patients, but the exact nature and level of immunodeficiency as well as its clinical, biological, and prognostic significance are still controversial. The applicant's long- range goal is to understand how the number and functional characteristics of mature and immature DC are regulated in health and various human disease states. The objective of this application is to investigate tumor-associated DC. The central hypothesis to be tested is whether tumor-induced impairment of effective antitumor immune response mediated by DC plays a substantive role in immune evasion and can be overcome by appropriate stimulation of DC generation, activity and protection from premature tumor-induced apoptosis. The rationale behind the proposed research centers on the clinical observations suggesting that DC infiltration within a number of tumors is often associated with an immune response against the tumor and an improved prognosis. Therefore, regulation of DC trafficking into and from tumor, antigen presentation, survival and interaction with other tumor-infiltrating cells must be understood before the regulation of anti-tumor immunity can be fully appreciated. To accomplish the objectives of this application, the applicant will pursue four specific aims: (1) narrow focus to DC and T cell infiltration, apoptosis and reciprocal interaction within tumors and investigate mechanism of T cell-mediated protection of DC from tumor-induced apoptosis; (2) determine the mechanism by which cytokines regulate DC homing in the tumor; (3) compare therapeutic efficacy of strategies designed to enhance DC number, survival or activity at the tumor site in murine model; (4) evaluate the therapeutic efficacy of FLT3L-based strategies designed to enhance DC number and survival in human clinical trials. The applicant expects to have determined how stimulation of DC generation in vivo or intratumoral administration of DC effects tumor growth both in murine models and human clinical trials. He additionally expects that protection of DC from tumor-induced apoptosis will significantly improve the therapeutic efficacy of DC-based immunotherapies. Finally, in addition to having application in understanding DC homing, interaction with T cells and survival in tumor microenvironment, it is expected that the results obtained will facilitate understanding of the etiology and pathogenesis of cancer and other chronic immune diseases.
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