Genetic and clinical characterization of B7‐H3 (CD276) expression and epigenetic regulation in diffuse brain glioma

Abstract

Gliomas are the most common malignant tumors of the brain. Immune checkpoints have been increasingly emphasized as targets for treating malignant tumors. B7‐H3 has been identified as an immune checkpoint that shows potential value for targeting therapies. We set out to characterize the expression pattern and biological function of B7‐H3 in brain gliomas using high‐throughput data obtained from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) projects. B7‐H3 was upregulated more in higher‐grade gliomas than that in lower‐grade gliomas in both CGGA and TCGA datasets. Isocitrate dehydrogenase (IDH) mutation seemed to exert significant influence on B7‐H3 expression in gliomas but led to quite different results between grade II gliomas and higher‐grade gliomas. In addition to IDH, methylation of B7‐H3 promoter and microRNA‐29 family also showed a potential regulatory effect on B7‐H3 expression. Gene ontology analysis revealed that B7‐H3 was associated with mitotic cell cycle, cell proliferation and immune response. Further investigation suggested that B7‐H3 was mostly involved in the Toll‐like receptor signaling pathway. Survival analysis indicated that B7‐H3 was an independent unfavorable prognosticator for glioma patients in both CGGA and TCGA datasets. B7‐H3 expression is regulated by multiple mechanisms and is potentially involved in the T‐cell receptor signaling pathway. Higher B7‐H3 expression indicates a worse prognosis for glioma patients, which warrants further research into the development of inhibitors for targeting this immune checkpoint, but we still need to be cautious about immune checkpoint inhibition for central nervous system tumors.

<p>B7-H3 Regulates Glioma Growth and Cell Invasion Through a JAK2/STAT3/Slug-Dependent Signaling Pathway</p>

“…14,16,31 Existing evidence also indicates that higher B7-H3 expression is tightly correlated with poor prognosis in glioma patients. 32 In this study, we further confirmed the role of B7-H3 in glioma development and invasion, which is consistent with previous reports for other tumor types. 33 We found that B7-H3 induced the activation of JAK2/STAT3 signaling through the upregulation of phosphorylated Src and inhibition of the negative regulators SHP-1 and SOCS-3.…”

The High Expression of CD276/HAVCR2 and CD163 is an Adverse Immune Subtype of Glioblastoma and is Closely Related to Epithelial-Mesenchymal Transition

“…Hence, an improved understanding of the possible causes of individual differences is needed to identify a subset of patients that may bene t from such treatments, thereby improving their current treatment. CD276 and HAVCR2 are key immune checkpoints in GBM, and its high expression is associated with poor prognosis in the patients [34,35,[39][40][41]. This observation is consistent with the results of this study.…”

<p>B7-H3 Induces Ovarian Cancer Drugs Resistance Through An PI3K/AKT/BCL-2 Signaling Pathway</p>

“…B7-H3 (CD276), a type I transmembrane protein belonging to the B7 family, is a glycoprotein consisting of 2 Ig-B7-H3 and 4 Ig-B7H3 isoforms in human. 3 B7-H3 is extensively known as a checkpoint molecular which is expressed on many tissues as well as immune cells. The enhanced expression of B7-H3 could down-regulate the type I interferon γ by T cells and reduce the cytotoxicity activity of NK cells, resulting in the immune suppression.…”