Escaping from immune surveillance and promoting of tumor vascular formation are essential for tumor growth and progression. Myeloid immune suppressor Gr+CD11b+ cells (MISCs) are significantly increased in peripheral blood, spleens and bone marrow of tumor bearing animals and cancer patients. They are unable to process and present antigens and therefore do not induce effective anti-tumor responses. Very recently, we have demonstrated a novel tumor-promoting role of these immune cells. MISCs infiltrate into tumors and constitute about 5% of total cells in murine tumors. They promote tumor vascular development through two mechanisms: 1) promoting tumor angiogenesis via production of MMP9, and deletion of MMP9 in these cells completely abolishes their tumor-promoting ability; 2) directly incorporated into tumor endothelium and contributed to tumor vascular formation through vasculogenesis. Consistent with this observation, MISCs acquire endothelial cell properties in the tumor microenvironment and proangiogenic culture conditions. Based on these findings, we hypothesize that alternative differentiation of MISCs is a strategy used by tumors to benefit their growth not only through immune suppression, but also by promoting tumor vascularization. This proposal will investigate the mechanisms and functional significance of MISCs in tumor vascular development and tumor progression.
Our specific aims are:
Specific Aim 1. Investigate the role of VEGF and Ang1 in MISC production, mobilization, recruitment to tumor sites and cell differentiation to endothelial cells in vivo.
Specific Aim 2. Determine the role and molecular mechanisms of VEGF and Ang1 in tumor-mediated MISC differentiation to endothelial cells in vitro.
Specific Aim 3. Explore the molecular mechanisms that regulate MMP9 expression in MISCs and its functional significance. The proangiogenic role of MISCs induced by tumors might constitute a critical mechanism by which tumors subvert their host. Accomplishment of this study will enhance our understanding of the biology of MISCs in tumor-host interaction. Interventions aimed at eliminating these cells may improve anti-tumor immune response and concurrently inhibit tumor vascular formation. ? ?
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