The presentation of tumor antigens and initiation of specific immune responses are the primary responsibility 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. 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 which dramatically inhibited the maturation of CD34+ hematopoietic stem cells into functional DC. One of the factors responsible for this defect was identified as tumor-derived vascular endothelial growth factor (VEGF). Preliminary data show that VEGF binding to the flt-1 receptor on hematopoietic stem cells may mediate reduced activity of the transcription factor NFkB, identifying the potential pathway responsible for this effect. The purpose of this application is to study tumor-associated defects in DC development in vitro and in vivo, and in particular to study the role of VEGF and its downstream signaling pathways in CD34+ stem cells. The ultimate goal of this project is to understand the role of these signals in DC differentiation and to develop immunotherapeutic strategies which counter this effect and enhance the effectiveness of immunotherapeutics in cancer patients. Specifically, in this project, the applicant will: 1) Characterize the nature of the cells derived from CD34+ cells in vitro after treatment with VEGF, and the possible role of other soluble factors in this process; 2) Assess the role of the VEGF receptor flt-1 in the inhibition of DC maturation in the presence of tumor-derived factors and that of the transcription factor NFkB in the defective functional maturation of dendritic cells in vitro; 3) Attempt to reproduce the inhibition of dendritic cell function in intact animals by prolonged infusion of recombinant VEGF alone or in combination with other factors; and 4) Test the efficacy of blockade of VEGF signaling on dendritic cell function, on the development of epitope-specific antitumor immunity, and on antitumor effects in syngeneic rodent tumor models.
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