CD200 is overexpressed in neuroblastoma and regulates tumor immune microenvironment

Patients with pediatric cancers such as neuroblastoma (NB) are often unresponsive to checkpoint blockade immunotherapy. One major factor in pediatric tumor resistance to immunotherapy is considered to be the low mutation rate of pediatric tumors. Another factor may be the overexpression of additional inhibitory pathways. While analyzing the RNA-sequencing database TARGET, we found that human NB tumors overexpress immune checkpoint molecule CD200. To determine its significance and impact on tumor immune microenvironment, we analyzed 49 cases of previously untreated, surgically removed NB tumors using immunohistochemistry and multi-color flow cytometry (FACS). We found that CD200 is overexpressed in more than 90% of NB tumors. In the tumor microenvironment of NB, CD200 is mainly overexpressed in CD45⁻ NB tumor cells, while its cognate receptor (CD200R) is mainly expressed in HLA-DR⁺CD14⁺ myeloid cells and CD11c⁺ dendritic cells. Low-level expression of CD200R is also observed in tumor-infiltrating CD4⁺ and CD8⁺ T cells. In NB tumors with higher CD200 expression (CD200^high), we observed lower numbers of HLA-DR⁺CD14⁺ myeloid cells and less tumor-infiltrating CD4⁺ and CD8⁺ T cells. Moreover, we found that CD4⁺ and CD8⁺ T cells produced less IFN-γ and/or TNF-α in CD200^high NB tumors. Thus, CD200–CD200R pathway appears to downregulate anti-tumor immunity in the tumor microenvironment of NB tumors, and blockade of this pathway may be beneficial for NB patients.