Costimulatory protein 4IgB7H3 drives the malignant phenotype of glioblastoma by mediating immune escape and invasiveness

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: In order to characterize B7H3 in glioblastoma we perform 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 as well as 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 immuno-suppressive 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 subcutaneous injected LN-229 cells, which were more susceptible to NK-cell mediated cytotoxicity compared with unsilenced control cells. Conclusions: Because of its immunosuppressive and proinvasive function, 4IgB7H3 may serve as a therapeutic target in the treatment of glioblastoma.