Abstract

CD200-Expresson on Vascular Endothelial cells is Mediated Through VEGF

Michael Olin, , University of Minnesota

Central nervous system tumors are the number one killer of children with cancer. Among those, glioblastoma multiforme (GBM) is an incurable primary brain tumor. The standard of care consists of resection followed by radiation and chemotherapy using temozolomide and is associated with a median overall survival of 14.6 months. To overcome this dismal outcome, clinicians are turning to immunotherapy approaches, which have demonstrated promising results in other solid tumors. However, immunosuppression by the tumor microenvironment prohibits a durable anti-tumor response and the optimization of immunotherapy, especially in GBM. Tumors have capitalized on immune regulatory mechanisms that facilitate the inhibition of an immune response. The CD200 checkpoint includes the tumor-bound protein CD200 and its inhibitory receptor. We recently reported that CD200 is also expressed on tumor vascular endothelial cells and that this expression is upregulated by VEGF, creating an immunological barrier around the tumor microenvironment. CD200 is also shed by tumors, and it has been reported that this soluble CD200 interacts with its inhibitory receptor restricted to immune cells to create an immunosuppressive environment. However, as extracellular proteases are abundant in the sera, it is highly probable for the soluble CD200 to be degraded. We hypothesis is that tumor-derived extracellular vesicles modulate CD200-induced immunosuppression. There is abundant evidence in the literature that extracellular vesicles derived from tumors suppress antigen-specific and non-specific anti-tumor responses, mediating a broad array of detrimental effects on the immune system. We now know that tumor-derived extracellular vesicles contain CD200 and VEGF. In addition, others have reported that miR-150, which plays a role in tumorigenesis, interacts with TAMs to induce VEGF, suggesting a link between tumor-derived extracellular vesicles, and the upregulation of C200. We propose i) CD200-expressing tumor-derived extracellular vesicles induce immune suppression, ii) VEGFpos-tEVs upregulates CD200 on vascular endothelial cells and/or iii) miR150 interaction with tumor associated macrophage upregulate CD200 on vascular endothelial cells maintain an immune suppressive tumor microenvironment.