CD200 in CNS tumor-induced immunosuppression: the role for CD200 pathway blockade in targeted immunotherapy

Abstract

BackgroundImmunological quiescence in the central nervous system (CNS) is a potential barrier to immune mediated anti-tumor response. One suppressive mechanism results from the interaction of parenchyma-derived CD200 and its receptor on myeloid cells. We suggest that CD200/CD200R interactions on myeloid cells expand the myeloid-derived suppressor cell (MDSC) population and that blocking tumor-derived CD200 will enhance the efficacy of immunotherapy.MethodsCD200 mRNA expression levels in human brain tumor tissue samples were measured by microarray. The amount of circulating CD200 protein in the sera of patients with brain tumors was determined by ELISA and, when corresponding peripheral blood samples were available, was correlated quantitatively with MDSCs. CD200-derived peptides were used as competitive inhibitors in a mouse model of glioblastoma immunotherapy.ResultsCD200 mRNA levels were measured in human brain tumors, with different expression levels being noted among the sub groups of glioblastoma, medulloblastoma and ependymoma. Serum CD200 concentrations were highest in patients with glioblastoma and correlated significantly with MDSC expansion. Similarly, in vitro studies determined that GL261 cells significantly expanded a MDSC population. Interestingly, a CD200R antagonist inhibited the expansion of murine MDSCs in vitro and in vivo. Moreover, inclusion of CD200R antagonist peptide in glioma tumor lysate-derived vaccines slowed tumor growth and significantly enhanced survival.ConclusionThese data suggest that CNS-derived tumors can evade immune surveillance by engaging CD200. Because of the homology between mouse and human CD200, our data also suggest that blockade of CD200 binding to its receptor will enhance the efficacy of immune mediated anti-tumor strategies for brain tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-014-0046-9) contains supplementary material, which is available to authorized users.

Single vs. combination immunotherapeutic strategies for glioma

“…Furthermore, it was shown that only combination therapy resulted in increased production of IFN-γ by CD4+ T cells and reduced proportions of T regs , suggesting immunostimulatory effects beyond inhibition of immunosuppressive myeloid cells 69 .MDSC inhibition may also improve the efficacy of vaccination therapy. Patients with glioblastoma show increased serum concentrations of CD200, a glycoprotein significantly correlated with MDSC expansion through its interaction with CD200R 70 . Combination of a CD200R antagonist with tumor lysate vaccination in GL261 glioma bearing mice resulted in reduced tumor growth and enhanced survival when compared to vaccination with tumor lysate alone 70 .…”

“…Patients with glioblastoma show increased serum concentrations of CD200, a glycoprotein significantly correlated with MDSC expansion through its interaction with CD200R 70 . Combination of a CD200R antagonist with tumor lysate vaccination in GL261 glioma bearing mice resulted in reduced tumor growth and enhanced survival when compared to vaccination with tumor lysate alone 70 .…”

CD200 immune checkpoint reversal at the site of tumor vaccine inoculation: A novel approach to glioblastoma immunotherapy

“…6,7,8,9 The CD200 immune checkpoint results in suppression of the secretion of proinflammatory cytokines, including IL2 and IFNg, 10,11 and increases production of myeloid derived suppressor cells (MDSCs) 12 and T regulatory cells (Tregs), 12,13,14 resulting in compromised anti-tumor activity. Previously, we revealed the following mechanisms employed by the CD200 protein: (1) it is upregulated in GBM-associated endothelial cells, creating an immunological barrier around the tumor microenvironment; 10 and (2) it is shed from tumors 12,15 and interacts with the inhibitory CD200 receptor (CD200R1) on immune cells in the tumor microenvironment and within the draining lymph nodes. 10,15 Our research focuses on the development of a therapeutic agent that targets the CD200 immune checkpoint regulatory system, which modulates the immune response through CD200R1.…”

Checkpoint Proteins in Pediatric Brain and Extracranial Solid Tumors: Opportunities for Immunotherapy

“…In a murine glioma model, mice treated with a CD200 antagonist with OVA+poly:ICLC, which induces an antigen specific cellular immune response, had prolonged survival compared to untreated mice. Treated mice had increased numbers of antigen-specific T cells and production of tumor necrosis factor-α and IFN-γ implicating CD200 in suppressing the immune response (59). Several pediatric brain tumor types including ependymoma, medulloblastoma and DIPG had higher CD200 expression by western blot compared to normal brain tissue (59).…”

“…Treated mice had increased numbers of antigen-specific T cells and production of tumor necrosis factor-α and IFN-γ implicating CD200 in suppressing the immune response (59). Several pediatric brain tumor types including ependymoma, medulloblastoma and DIPG had higher CD200 expression by western blot compared to normal brain tissue (59). Increased CD200 mRNA expression was seen in supratentorial compared to posterior fossa ependymoma and in group 4 compared to Shh or group 3 medulloblastoma.…”