Different defects of the immune system in cancer patients have been well documented, 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 dendritic cells (DC) are regulated in health and various human diseases. The objective of this application is to identify mechanisms involved in inhibition of DC generation, differentiation and survival in the tumor microenvironment. The central hypothesis to be tested is that tumor-induced dysfunction of effective antitumor immune responses is mediated by suppression of DC generation and survival and can be overcome by an appropriate regulation of DC production and activity. The rationale behind the proposed research centers on the clinical observations suggesting that DC infiltration within a number of tumors is associated with an immune response against the tumor and an improved prognosis. Therefore, regulation of DC generation, differentiation, survival and function in the tumor-bearing host 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) Determine whether sensitivity of DC to the tumor-induced apoptosis depends on the stage of DC maturation and identify molecular and cellular mechanisms responsible for this effect, (2) Determine whether tumor-derived factors inhibit DC generation and identify factors and mechanisms responsible for tumor-mediated inhibition of DC generation and the role of cytokines in the regulation of dendropoiesis in the tumor environment (3) Compare therapeutic efficacy of strategies designed to protect DC generation and function in murine tumor models and determine mechanisms involved in DC protection by cytokines, and (4) Conduct clinical trials based on strategies designed to protect DC generation and increase DC survival in neuroblastoma patients. The applicant expects to have determined how the stimulation of DC generation in vivo affects tumor growth. He additionally expects, that protection of DC generation and function from tumor-induced inhibition significantly improves the therapeutic efficacy of DC-based immunotherapies. Finally, in addition to having application in understanding DC differentiation and survival in the 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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