Inter-regulatory function of immune-modulation and angiogenesis in cancer

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PROJECT SUMMARY There is mounting evidence that tumors recruit various innate immune cells where they become an additional source of chemokines and cytokines to promote angiogenesis, invasion and metastasis as demonstrated in numerous preclinical tumor models. Importantly, like wounds, tumors attract innate immune cells that, rather than promoting the cytotoxic clearance of tumor cells, become immune-suppressive and angiogenic and elicit a tumor-promoting inflammatory response. In lieu of the fact that the regulation of angiogenesis and immunosuppression coincides in myeloid cells, one goal of this proposal is to test the hypothesis that the efficacy of antiangiogenic therapy hinges on fostering an immune-stimulatory environment and that concurrent use of immunomodulating molecules and agents can prevent or reverse resistance to angiogenic inhibitors leading to a more durable response to therapy. Based on our published and preliminary results, we further propose that blocking VEGF signaling promotes immune stimulation by altering the tumor vasculature to allow lymphocyte infiltration into the tumor and by polarizing immune cells to an Th1 phenotype by which they enhance the secretion of the chemokine CXCL14 blocking vessel sprouting and supporting the maturation of dendritic cells. In response, tumors enhance the secretion of factors that activate the PI3K and other immune- modulating pathway in myeloid cells restating an immune-suppressive and proangiogenic phenotype in myeloid cells that renders them non-responsive to antiangiogenic therapy and generates a proangiogenic tumor relapse. As a the first goal we intend to elicit the functional significance of the induction of CXCL14 in myeloid-driven tumor response as well as the induction of PDL1 and other immuneregulatroy pathways (e.g. Stat3 and NFkB pathways) factors in tumor relapse to antiangiogenic therapy. The second goal of this study will be then to therapeutically induce an enduring immunestimulating tumor environment by polarizing immune cells and modulating the tumor vessels to become reminiscent of high-endothelial venules that are specialized to promote lymphocyte trafficking. We propose that this will enable sufficient infiltration of activated cytotoxic T- cells and more sufficiently eradicate tumors and metastases.