Costimulatory Protein 4IgB7H3 Drives the Malignant Phenotype of Glioblastoma by Mediating Immune Escape and Invasiveness

Abstract

Purpose: Recent work points out a role of B7H3, a member of the B7-family of costimulatory proteins, in conveying immunosuppression and enforced invasiveness in a variety of tumor entities. Glioblastoma is armed with effective immunosuppressive properties resulting in an impaired recognition and ineffective attack of tumor cells by the immune system. In addition, extensive and diffuse invasion of tumor cells into the surrounding brain tissue limits the efficacy of local therapies. Here, 4IgB7H3 is assessed as diagnostic and therapeutic target for glioblastoma.Experimental Design: To characterize B7H3 in glioblastoma, we conduct analyses not only in glioma cell lines and glioma-initiating cells but also in human glioma tissue specimens.Results: B7H3 expression by tumor and endothelial cells correlates with the grade of malignancy in gliomas and with poor survival. Both soluble 4IgB7H3 in the supernatant of glioma cells and cell-bound 4IgB7H3 are functional and suppress natural killer cell-mediated tumor cell lysis. Gene silencing showed that membrane and soluble 4IgB7H3 convey a proinvasive phenotype in glioma cells and glioma-initiating cells in vitro. These proinvasive and immunosuppressive properties were confirmed in vivo by xenografted 4IgB7H3 gene silenced glioma-initiating cells, which invaded significantly less into the surrounding brain tissue in an orthotopic model and by subcutaneously injected LN-229 cells, which were more susceptible to natural killer cell-mediated cytotoxicity than unsilenced control cells.Conclusions: Because of its immunosuppressive and proinvasive function, 4IgB7H3 may serve as a therapeutic target in the treatment of glioblastoma.

B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

“…The growth of established B7-H3 knockdown Maver and Z138 xenografts slowed down compared with their NC groups by 59.1 and 65.0% at the end of observation, respectively. The similar growth inhibition of B7-H3-knockdown xenografts in glioma (22), breast cancer (26) and pancreatic cancer (23) has been observed in other reseach. Furthermore, we found that the expressions of Ki-67 and PCNA were significantly decreased in the B7-H3 silenced MCL xenografts.…”

“…Tekle et al demonstrated that the B7-H3 silencing reduced metastatic capacity of MDA-MB-435 melanoma cells and significantly increased the survival of nude mice (20). Other studies also reported that B7-H3 was important in regulating the adhesive, migratory, and invasive capacity in breast cancer (21), glioblastoma (22), pancreatic cancer (23), prostate cancer (24) and osteosarcoma (25). Liu et al discovered that silencing of B7-H3 sensitized the breast cancer cell lines to paclitaxel by abrogating Jak2/Stat3 phosphorylation (26).…”

A novel subset of B7-H3+CD14+HLA-DR−/lowmyeloid-derived suppressor cells are associated with progression of human NSCLC

“…15 In human cancer, B7-H3 is detected on tumor cells arising from diverse tissues, and the expression level of B7-H3 is associated with increased disease severity. 16,17 B7-H3 can therefore function as either a T-cell co-stimulator or co-inhibitor depending on the biological context. 18 The exact role of B7-H3 in human cancer remains to be further delineated.…”

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

“…A172 shQPRT cells were generated by transfection with the Origene shQPRT vector (Origene). T325 glioma-initiating cells were generated as described previously (23). HA1800 primary astrocytes were obtained from ScienCell.…”