CD200R blockade enhances anti-tumor immunity by unleashing NK and CD8⁺ T cells in tumor

Immune checkpoint inhibitors have revolutionized cancer therapy, but a large proportion of patients do not respond well to current checkpoint immunotherapies. CD200R (also known as OX2R) is a transmembrane glycoprotein of the immunoglobulin superfamily that is mainly expressed on myeloid and lymphoid-derived immunocompetent cells such as myeloid cells, natural killer (NK), and CD8⁺ T cells. In this study, we investigated the therapeutic potential and cellular mechanisms of targeting CD200R in tumor immunotherapy. We established 4 subcutaneous tumor mouse models using MC38 (colon cancer), MCA205 (fibrosarcoma), LLC (lung cancer), and EO771 (mammary cancer) cell lines. We found that CD200R was highly expressed on tumor-infiltrating NK and CD8⁺ T cells with exhausted phenotypes in the four subcutaneous tumor mouse models. Either genetic ablation or antibody blockade of CD200R retarded tumor growth and prolonged the survival of tumor-bearing mice by preventing or reversing exhaustion of both NK cells and CD8⁺ T cells. The combined therapy of CD200R antibody with anti-PD-1/anti-PD-L1 synergistically inhibited tumor growth. By depletion of NK or/and CD8⁺ T cells, we demonstrated that both cell types contributed to the anti-tumor efficacy of CD200R blockade in tumor-bearing mice. Further, the blockade of human CD200R significantly enhanced human NK cell function and inhibited human tumor growth in PBMC-reconstituted xenograft mice. Our results demonstrate that CD200R is a potential immune checkpoint molecule that can suppress the tumoricidal activities of NK and CD8⁺ T cells, and could thus be exploited as a therapeutic target in the future.