The presentation of tumor antigens and initiation of specific immune responses are the primary responsibilities of professional antigen presenting cells. Dendritic cells (DC) are the most potent antigen presenting cells, and play a crucial role in the induction of primary immune responses. DC are considered one of the best vehicles for delivery of tumor-specific antigens in immunotherapy of cancer. Recently, the applicant and others have demonstrated defective DC function in tumor-bearing animals and in cancer patients. These defects were caused, at least in part, by tumor-derived factors that dramatically inhibited the maturation of CD34+ hematopoietic stem cells into functional DC. The applicant's preliminary data demonstrated defective DC maturation in tumor-bearing mice that might in part be responsible for defective DC function. His preliminary data also demonstrated the appearance of an as yet uncharacterized immature myeloid cell in the dendritic cell fraction from peripheral blood of patients with different types of cancer. All these data suggest that there is a serious defect in DC maturation in cancer. This defect may lead to the production of immature and functionally defective cells. He hypothesizes that these cells also may be involved in active immunosuppression. The presence of these cells may seriously compromise any efforts in immunotherapy of cancer by affecting the function of the host immune system and contaminating the population of DC used in immunotherapy. The purpose of this application is to study tumor-associated defects in DC development in vivo. The ultimate goal of this project is to understand the role of these signals in DC differentiation and to develop immunotherapeutic strategies that counter this effect and enhance the effectiveness of immunotherapeutics in cancer patients. Specifically, the applicant proposes to 1) Characterize the nature of the immature myeloid and immature dendritic cells appearing in peripheral blood of patients with breast, lung and head and neck cancer, and establish the clinical relevance of these cells; 2) Investigate the ability of the immature dendritic cells to suppress immune response and the function of dendritic cells in lymph nodes in patients with cancer; and 3) Study the therapeutic approaches to correct defective DC function in cancer.
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