The Immunosuppressive Surface Ligand CD200 Augments the Metastatic Capacity of Squamous Cell Carcinoma

Abstract

CD200 (OX-2) is a cell surface glycoprotein that imparts immune privileges by suppressing alloimmune and autoimmune responses through its receptor, CD200R, expressed primarily on myeloid cells. The ability of CD200 to suppress myeloid cell activation is critical for maintaining normal tissue homeostasis but may also enhance the survival of migratory neoplastic cells. We show that CD200 expression is largely absent in welldifferentiated primary squamous cell carcinoma (SCC) of the skin, but is highly induced in SCC metastases to the lymph node and other solid tissues. CD200 does not influence the proliferative or invasive capacity of SCC cells or their ability to reconstitute primary skin tumors. However, loss of CD200 impairs the ability of SCC cells to metastasize and seed secondary tumors, indicating that the survival of CD200 + SCC cells may depend on their ability to interact with CD200R + immune cells. The predominant population of CD200R + stromal cells was CD11b + Gr-1 + myeloid-derived suppressor cells, which release elevated levels of granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor when in the presence of SCC cells in a CD200-dependent manner. Collectively, our findings implicate CD200 as a hallmark of SCC metastasis and suggest that the ability of CD200 + SCC keratinocytes to directly engage and modulate CD200R + myeloid-derived suppressor cells is essential to metastatic survival. Cancer Res; 70(7); 2962-72. ©2010 AACR.

CD200:CD200R-Mediated Regulation of Immunity

“…Importantly and consistent with the hypothesis that CD200:CD200R interactions in this model suppress a host antitumor response able to regulate both local and distant tumor growth, CD200R1KO mice showed reduced tumor growth and metastasis, while optimal tumor immunity (and suppression of metastasis) was seen in CD200R1KO mice receiving inocula of CD200-EMT6 tumor cells [159]. This idea that CD200 expression may be relevant to regulation of tumor metastasis was confirmed independently by Stumpfova, in a skin squamous cell carcinoma study [154].…”

“…Current studies are underway to characterize the nature of the sCD200 and to explore in more details the mechanism(s) responsible for control of CLL growth in vivo in NOD·SCID γ2r−/− mice. In addition to expression of CD200 on the cell surface of hematologic tumors, it has now become apparent that CD200 is also expressed in many solid malignancies, including subsets of melanomas, breast cancer, renal cell carcinomas and ovarian tumors [153], squamous cell carcinomas [154], and, most interestingly, in the so-called cancer stem cells (CSCs) within the solid tumor [155]. In this latter case it has been proposed that CD200 expression plays a role in the ability of a CSC to escape the immune system [156].…”

Coinhibitory molecules in hematologic malignancies: targets for therapeutic intervention

“…81 Its ligand, CD200 (OX2), is a glycoprotein expressed on a broad number of cell types, including solid tumors and hematologic malignancies. 82,83 In addition to the previously discussed coinhibitory molecules, CD200R inhibits both T-and NK-cell functionality. 84,85 Furthermore, CD200/CD200R interactions are involved in tumor immune evasion, as CD200 expression on AML cells promoted tumor growth in mice.…”

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

“…24 Briefly, the syngeneic splenocytes were divided into equal numbers and either loaded with 1 lg/ml cytotoxic T lymphocyte (CTL) epitope peptide (human Her-2/neu p63 [TYLPTNASL] peptide or a mixture of E6 [41][42][43][44][45][46][47][48][49][50] [EVYD-FAFRDL] and E7 [49][50][51][52][53][54][55][56][57] [RAHYNIVTF] peptides) or left unpulsed. Peptide-pulsed splenocytes were labeled with chloromethylfluorescein diacetate succinimidyl ester (CFSE; Invitrogen, Carlsbad, CA) at 20 lM, and unpulsed splenocytes were labeled with 2 lM CFSE.…”