Cancer immunotherapy has demonstrated promising results. However, to date, researchers have failed to overcome the complex interplay between the immune system and the immune suppressive tumor microenvironment. Progression to a productive immune response involves passing a number of immunological checkpoints, which act as barriers for productive immunotherapies. To overcome this limitation, the FDA-approved monoclonal antibodies, ipilimumab, pembrolizumab and nivolumab, respectively, which inhibits the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD1) and programmed death 1 ligand (PD-L1) checkpoints. Both anti-CTLA4 and anti-PD1 act directly on T cells. In contrast, a third immunological checkpoint act directly on antigen presenting cells inducing T-cell tolerance. This checkpoint arises from the engagement of CD200 and it’s receptor (CD200R). CD200 is expressed in a variety of human tumors including melanoma and glioblastomas. However, it is the soluble form of CD200 that correlates with poor patient outcome. We reported that CD200 concentration significantly increased in the sera of glioma patients as their tumors progressed, which correlated with increased lineage negative myeloid derived suppressor cell (MDSC) population. We developed an inhibitor of the CD200 (CD200R antagonist) that acts directly on the CD200R on antigen presenting cells overpowering the suppressive properties of CD200. Our CD200R antagonist inhibits myeloid derived suppressor cell expansion, enhances cytokine and chemokine production significantly enhancing survival in both glioma and breast carcinoma tumor models.