A critical role of CD200R signaling in limiting the growth and metastasis of CD200 positive melanoma

Abstract

Abstract CD200 is a cell surface glycoprotein that functions through engaging CD200 receptor on cells of the myeloid lineage and inhibits their functions. Expression of CD200 has been implicated in a variety of human cancer cells including melanoma cells and has been thought to play a protumor role. However, our previous studies using B16 melanoma and J558 plasmacytoma models suggest that tumor expressed CD200 may inhibit tumor growth and metastasis via shaping tumor microenvironment. In this study, we have further evaluated the role of CD200R signaling in tumor growth and metastasis using CD200R-deficient mice. We found that CD200R-deficient mice exhibited accelerated growth of CD200-positive, but not CD200-negative B16 tumors. Strikingly, CD200R-deficient mice receiving CD200-positive B16 cells intravenously exhibited massive tumor growth in multiple organs including liver, lung, kidney and peritoneal cavity, while the growth of the same tumors in wild type mice is limited. CD200-positive tumors grown in CD200R-deficient mice contained higher numbers of CD11b+Ly6C+ myeloid cells, exhibited increased expression of VEGF and HIF-1a genes with increased angiogenesis and showed significantly reduced infiltration of CD4+ and CD8+ T cells. The Liver from CD200R-deficient mice under metastatic growth of CD200-positive tumors contained significantly increased numbers of CD11b+Gr1− myeloid cells, FoxP3+ regulatory T cells; liver T cells also had reduced capacity in the production of IFN-g or TNF-a. Taken together, we have revealed critical roles of CD200R signaling in limiting the growth and metastasis of CD200 positive tumors.