To study SDF-1/CXCR4 in human tumors, we isolated immune cells in ascites and lymph nodes of patients with ovarian carcinomas. We will present extensive evidence suggesting significant and previously unknown roles for SDF-1/CXCR4 signals in tumor immunopathogenesis through distinct immune effects on plasmacytoid dendritic cells (PDC) and regulatory T cells (Tregs).Thus, SDF-1/CXCR4 signals may be a final common pathway mediating significant and diverse tumor immunopathologic mechanisms. We hypothesize that SDF-1/CXCR4 interactions play a significant role in ovarian cancer pathogenesis by enhancing immune evasion, metastasis, tumor growth and neoangiogenesis. This hypothesis predicts that interrupting SDF-1/CXCR4 signals will be therapeutic through several distinct mechanisms, not just by blocking metastasis. Prior studies of chemokines have been hampered by promiscuity: one chemokine may bind several receptors, and one receptor may bind several distinct chemokines. However, SDF-1/CXCR4 is a unique ligand/receptor pair. Thus, study of this interaction is tractable, and offers significant opportunities to test the effects of blocking such interactions as an anti-tumor strategy in a model where definitive conclusions regarding ligand/receptor interactions can be drawn. This proposal focuses on immunological aspects of this interaction. Our over-arching hypothesis is that the net effect of blocking SDF-1/CXCR4 is to reduce tumor burden through augmenting tumor-specific immunity. Tumors also express cytokines (IL-l0 and TGF-beta) and ligands (B7-H1) that may induce Treg differentiation. Thus, we hypothesize that the tumor itself is an alternative or complementary source of Treg differentiation. Tumor SDF-1 may play a significant role in this regard.
Our specific aims : 1. Test the hypothesis that SDF-1/CXCR4 signals mediate immunopathology through control of PDC migration, survival or function in vivo. 2. Test the hypothesis that SDF-1/CXCR4 signals mediate immunopathology through control of Treg migration, survival or function in ovarian cancer. 3. Test the hypothesis that the net effect of blocking SDF-1/CXCR4 is to reduce tumor burden through augmenting tumor-specific immunity using our well-defined TAA-specific systems. 4. Test the hypothesis that SDF-1/CXCR4 signals mediate Treg differentiation in tumors. We will use SDF-1( MMC and LM-1 tumors and their SDF-1- derivatives produced using siRNA technology.
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