Reduction of CD200 expression in glioma cells enhances microglia activation and tumor growth

Abstract

CD200, a type I transmembrane glycoprotein, can interact with its receptor CD200R, which plays an inhibitory role in the activation of microglia-the resident macrophages of the central nervous system. In this study, the rat C6 glioma cell line (C6-1) that was previously characterized with high in vivo tumorigenicity was found to generate CD200 mRNA abundantly. However, CD200 expression was barely detected in another C6 glioma cell clone (C6-2) that was previously found to display low tumorigenic behavior. The results from CD200 immunohistochemistry on human glioma tissue array also showed that tumor cells in Grade I-II astrocytoma expressed a lower level of CD200 immunoreactivity than those detected in Grade III-IV glioblastoma multiforme. C6-1 transfectants with stable downregulation of CD200 gene expression using lentivirus knockdown approach were generated (C6-KD). Microglia and iNOS cells were increased when microglia were co-cultured with C6-KD cells. The colony formation of C6-KD was also augmented when those cells were co-cultured with microglia. Yet, increased colony formation of C6-KD transfectants in the co-culture with microglia was effectively suppressed by interleukin (IL)-4 and IL-10. The in vivo results indicated that the tumor formation of C6-1 cells in rat brain was promoted after CD200 gene knockdown. Moreover, CD11b activated microglia and iNOS microglia were highly accumulated in the tumor site formed by C6-KD. In conclusion, our findings demonstrate that the downregulation of CD200 expression in CD200-rich glioma cells could foster the formation of an activated microglia-associated tumor microenvironment, leading to glioma progression. © 2016 Wiley Periodicals, Inc.

Profiling of inhibitory immune checkpoints in glioblastoma: Potential pathogenetic players

“…CD200 is a type I transmembrane glycoprotein that plays an inhibitory role in the activation of microglia. For this reason, many studies have shown that its expression is enhanced in brain tumors ( 32 ), and especially in higher grade tumors ( 33 ). However, its role is still controversial, indeed in the same study Wang et al ( 33 ) found that CD200 down-expression can lead to a particular microglia tumor microenvironment that promotes tumor progression, in agreement with our results.…”

“…For this reason, many studies have shown that its expression is enhanced in brain tumors ( 32 ), and especially in higher grade tumors ( 33 ). However, its role is still controversial, indeed in the same study Wang et al ( 33 ) found that CD200 down-expression can lead to a particular microglia tumor microenvironment that promotes tumor progression, in agreement with our results. Recent studies in dogs also showed that targeting CD200, enhanced the capacity of antigen-presenting cells to prime T-cells to mediate an anti-glioma response ( 34 ).…”

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

“…CD200 is a type I transmembrane glycoprotein and can interact with its receptor CD200R, which plays an inhibitory role in the activation of microglia of the central nervous system. The downregulation of CD200 expression in CD200-rich glioma cells could foster the formation of an activated microglia-associated tumor microenvironment, leading to glioma progression [ 33 ]. P-selectin mediates microglia-enhanced GBM proliferation and invasion by altering the microglia/macrophages’ activation state.…”

The Immune Checkpoint Molecule CD200 Is Associated with Tumor Grading and Metastasis in Bladder Cancer

“…After their interaction, immune response is negatively regulated by suppression of T-cell response. Thus, CD200 and its receptor represent promising targets to improve therapy in immune-mediated as well as oncological diseases (30)(31)(32)(33).…”