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 well-differentiated 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.