Costimulatory Protein 4IgB7H3 Drives the Malignant Phenotype of Glioblastoma by Mediating Immune Escape and Invasiveness
Costimulatory Protein 4IgB7H3 Drives the Malignant Phenotype of Glioblastoma by Mediating Immune Escape and Invasiveness
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DOI：
10.1158/1078-0432.ccr-11-0880
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发表时间：
2012-01-01
影响因子：
11.5
通讯作者：
Wick, Wolfgang
中科院分区：
文献类型：
--
作者：
Lemke, Dieter;Pfenning, Philipp-Niclas;Wick, Wolfgang
目的：最近的工作指出了B7 H3，共刺激蛋白B7家族的成员，在各种肿瘤实体中传递免疫抑制和增强侵袭力的作用。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受损和无效攻击。此外，肿瘤细胞向周围脑组织的广泛和弥漫性侵袭限制了局部治疗的功效。在这里，4 IgB 7 H3被评估为诊断和治疗的目标为glioblastoma.Experimental Design：为了表征B7 H3在胶质母细胞瘤，我们进行分析，不仅在胶质瘤细胞系和胶质瘤起始细胞，但也在人脑胶质瘤组织标本。胶质瘤细胞上清液中的可溶性4 IgB 7 H3和细胞结合的4 IgB 7 H3都是功能性的，并且抑制自然杀伤细胞介导的肿瘤细胞溶解。基因沉默表明，膜和可溶性4 IgB 7 H3在体外胶质瘤细胞和胶质瘤起始细胞中传递促侵袭表型。通过异种移植的4 IgB 7 H3基因沉默的胶质瘤起始细胞（其在原位模型中显著较少侵入周围脑组织）和皮下注射的LN-229细胞（其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）在体内证实了这些促侵袭和免疫抑制特性。由于其免疫抑制和促侵袭作用，4 IgB 7 H3可能作为胶质母细胞瘤治疗的靶点。临床癌症研究; 18（1）; 105-17。(C)2011年AACR。
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. Clin Cancer Res; 18( 1); 105-17. (C) 2011 AACR.