IMMU-14. TARGETING CD200 ACTIVATION RECEPTORS TO OVERCOME THE IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT

Abstract

Glioblastoma multiforme is an incurable primary brain tumor. The current standard of care consists of resection followed by radiation and chemotherapy; associated with a median overall survival of 14.6 months. To overcome this dismal outcome, clinicians are turning to immunotherapeutic approaches, which have demonstrated promising results in non-CNS tumors. Recently, the FDA approved immune checkpoint inhibitor therapy for solid tumors that is otherwise refractory to standard therapy. Immune checkpoint inhibitor therapy has increased patient survival, heralding a new era for effective cancer treatment. We have recently reported that targeting an alternative immune checkpoint, CD200, inhibits tumor-induced immunosuppression without toxic side effects. We are targeting the CD200 checkpoint, which uses paired receptors (inhibitory and activation receptors) to maintain homeostasis. We demonstrated that targeting the activation receptors (CD200AR) surmounts the CD200-induced inhibitory signals, priming a potent anti-tumor response. Although the suppressive mechanism between the CD200 protein and the inhibitory receptor has been well characterized, little is known involving the CD200 activation receptors. In its native state, CD200 only binds to its inhibitory receptor, CD200R1; however, we identified multiple metalloprotease (MMP) cleavage sites within the CD200 protein. We hypothesize that MMP cleavage releases protein fragments and alters CD200 folding, exposing binding sites for the CD200AR. We developed peptide ligands to target the CD200ARs, designated as CD200AR-L. In our murine model, we reported enhanced T-cell responses with the use of the murine CD200AR-L’s. In contrast, similarly treated cells with the CD200 activation receptors knocked out or wildtype cells pulsed with a scrambled CD200AR-L failed to respond. IMPACT: Our research is highly innovative in that it uniquely focuses on a novel mechanism that tumors exploit to escape immune surveillance. The ultimate objective of this research is to understand the underlying mechanism of the CD200 blockade for effective implementation of immunotherapy against CNS tumors.