Clinical Cooperation Unit Neurooncology, German Cancer Research Center, University Hospital Heidelberg, Heidelberg, Germany.
Clin Cancer Res. 2012 Jan 1;18(1):105-17. doi: 10.1158/1078-0432.CCR-11-0880. Epub 2011 Nov 11.
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.
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.
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.
Because of its immunosuppressive and proinvasive function, 4IgB7H3 may serve as a therapeutic target in the treatment of glioblastoma.
最近的研究指出 B7H3（B7 家族共刺激蛋白的成员之一）在多种肿瘤实体中传递免疫抑制和强制侵袭的作用。胶质母细胞瘤具有有效的免疫抑制特性，导致免疫系统对肿瘤细胞的识别和攻击受损。此外，肿瘤细胞广泛而弥漫地侵袭周围脑组织，限制了局部治疗的效果。在这里，4IgB7H3 被评估为胶质母细胞瘤的诊断和治疗靶点。
为了研究 B7H3 在胶质母细胞瘤中的作用，我们不仅在神经胶质瘤细胞系和神经胶质瘤起始细胞中进行了分析，还在人胶质母细胞瘤组织标本中进行了分析。
肿瘤细胞和内皮细胞表达的 B7H3 与胶质瘤的恶性程度以及不良预后相关。胶质瘤细胞上清液中的可溶性 4IgB7H3 和细胞结合的 4IgB7H3 均具有功能，可抑制自然杀伤细胞介导的肿瘤细胞裂解。基因沉默表明，膜结合和可溶性 4IgB7H3 在体外传递神经胶质瘤细胞和神经胶质瘤起始细胞的侵袭表型。在体内，通过沉默 4IgB7H3 的神经胶质瘤起始细胞的异种移植实验证实了这些侵袭性和免疫抑制性特性，这些细胞在原位模型中侵袭周围脑组织的程度明显降低，而皮下注射的 LN-229 细胞比未沉默的对照细胞更容易受到自然杀伤细胞介导的细胞毒性作用。
由于其免疫抑制和侵袭性功能，4IgB7H3 可能成为胶质母细胞瘤治疗的一个治疗靶点。
