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ROLE OF VASCULAR ENDOTHELIAL GROWTH FACTOR ON DENDRITIC CELL FUNCTION: INTERPLAY BETWEEN ANGIOGENESIS AND ANTI-TUMOR IMMUNITY
Tumors are able to evade the immune system by establishing an immunosuppressive microenvironment, preventing the formation of a proper immune response. This immunosuppressive phenotype has been described in the tumors of patients with breast cancer and was shown to be the result of accumulation of CD4+CD25+ T regulatory lymphocytes and upregulation of inhibitory cytokines. Strong evidence suggests that impairment of dendritic cell (DC) function plays a major role in the onset and evolution of the immunosuppressive tumor microenvironment. Tumor associated DC function can be inhibited through suppression of DC maturation and/or through inhibition of DC recruitment and infiltration to the tumor. Significant evidence supports that vascular endothelial growth factor (VEGF), a potent angiogenic factor, is involved in immune evasion by modulating leukocyte adhesion and recruitment but also by exerting specific effects on bone marrow derived progenitor cells and on DC maturation. In this project we propose to assess the link between VEGF, alteration of tumor associated DC function and antitumor immunity in breast cancer, assessing the contribution of VEGFR1 and VEGFR2. We aim to investigate the mechanisms underlying VEGF-mediated inhibition of tumor associated DC function, focusing on DC maturation and DC recruitment. We propose to block VEGFR1 and VEGFR2 signaling in vivo using specific antibodies and assess tumor infiltrated DC recruitment, maturation and function.
Research has shown that breast cancer is able to suppress the immune system preventing the activation and expansion of immune effector cells that would specifically target the cancer cells. This immunosupression is mediated by the significant recruitment of specific immunosupressor cells and by the release of inhibitory signals. Dendritic cells are important immune cells that control the initiation phase of the immune response, failure of which not only prevents the formation of an active immune response but can also generate immunosupressive cells and signals. In this study we propose to investigate the mechanisms by which cancers are able to inhibit dendritic cell function. We will also block a key player in this process, reversing the inhibition in an attempt to boost the antitumor immune response.