A Critical Role for CD200R Signaling in Limiting the Growth and Metastasis of CD200+ Melanoma

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. However, its roles in tumor growth and immunity are not clearly understood. In this study, we have used CD200R-deficient mice and the B16 tumor model to evaluate this issue. 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-1α genes with increased angiogenesis and showed significantly reduced infiltration of CD4+ and CD8+ T cells, presumably due to reduced expression of T cell chemokines such as CXCL9 and CXCL16. 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 and reduced numbers of NK cells. Liver T cells also had reduced capacity in the production of IFN-γ or TNF-α. Taken together, we have revealed a critical role of CD200R signaling in limiting the growth and metastasis of CD200 positive tumors. Targeting CD200R signaling may thus has a potential to interfere with the metastatic growth of CD200-positive tumors like melanoma.

NK Cell-Based Immune Checkpoint Inhibition

“…It recognizes CD200 as its ligand, which is expressed on various normal tissues such as the central nervous system, retina, hair follicular cells, vascular endothelial cells, and thymocytes, as well as activated T, B, and DCs, in addition to its expression on various tumors (265). CD200 is considered as a marker of tumor progression since it is overexpressed on various cancers of both hematopoietic and non-hematopoietic origin, such as acute myeloid leukemia, multiple myeloma, hairy cell leukemias, B cell chronic leukemias, melanoma, and ovarian, rectal cancer, and bladder cancer, and its expression is associated with the worst prognosis (266)(267)(268)(269)(270)(271)(272)(273)(274). Moreover, CD200 expression can also be induced on cancer cells (275,276).…”

Inhibitory CD200-receptor signaling is rewired by type I interferon

“…However, the CD200R-CD200 axis has also been reported as a co-stimulatory axis (Borriello et al, 1997;Wang et al, 2019). Furthermore, CD200R is required to 'license' TLR2mediated immune activation by Herpes Simplex Virus 1 in macrophages (Soberman et al, 2012), and the CD200R/CD200 axis in some cases was suggested to regulate protective antitumor responses (Erin et al, 2015;Erin et al, 2018;Liu et al, 2016). Taken together, although CD200R is generally considered to be an inhibitory receptor, there are data that suggest a more versatile and/or complex functionality of CD200R.…”

Analysis of infantile fibrosarcoma reveals extensive T‐cell responses within tumors: Implications for immunotherapy

“…2B), which is considered to be a negative regulator of T-cell function through interaction with CD200 expressed in various cells. [28][29][30] This observation suggests that targeting CD200-CD200R may have a potential to further enhance antitumor T-cell responses in IFS patients.…”