TB-01CD200 CHECKPOINT BLOCKADE PLAYS AN IMPORTANT ROLE IN CNS TUMOR IMMUNOEDITING

Abstract

Many recognize that the effectiveness of tumor-derived vaccines for CNS tumors is limited by checkpoint blockades, however CD200 has been overlooked to date. CD200, a tumor-bound protein, is immunosuppressive when engaging its receptor, CD200R, by upregulating peptidylprolyl isomerase A (PPIA). CD200, expressed on vascular endothelial cells within WHO Grade III and IV astrocytomas, down-regulates T-cell activation. We developed a competitive CD200 inhibitor peptide to overcome CD200-induced immunosuppression. This inhibitory peptide inhibits PPIA upregulation, enhances cytokine and chemokine production, and significantly enhances survival in a murine GL261 model. The use of the peptide inhibitor along with anti-CD200R antibody demonstrated further benefit. Pulsing immature dendritic cells with the CD200 inhibitor enhanced MHC-II and CD86 expression and cytokine production. We have also seen tumor regression and enhanced survival in our canine glioma patients when the CD200 inhibitor was added to the immunotherapy protocol. IMPACT: We are the first to correlate CD200 in brain tumors and tumor-derived vaccines as an inhibitor of immune activation. Our data suggest that we are suppressing the immune system with the same vaccines designed specifically to induce an anti-tumor response. Tumor endothelial expression of CD200 is also a likely reason for escape fromnativeimmunesurveillanceand failureof other immunotherapeutic approaches. We are optimistic that use of our competitive inhibitor peptide againstCD200 andanti-CD200R antibody willultimatelylead to thedevelopment ofnoveltherapeuticsthatimprovetheefficacyof cancer immunotherapy.