B7-H4(B7x)-Mediated Cross-talk between Glioma-Initiating Cells and Macrophages via the IL6/JAK/STAT3 Pathway Lead to Poor Prognosis in Glioma Patients.
B7-H4(B7x)-Mediated Cross-talk between Glioma-Initiating Cells and Macrophages via the IL6/JAK/STAT3 Pathway Lead to Poor Prognosis in Glioma Patients.
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B7-H4(B7x)介导的胶质瘤起始细胞和巨噬细胞之间通过IL6/JAK/STAT3途径的串扰导致胶质瘤患者预后不良
DOI：
10.1158/1078-0432.ccr-15-0858
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发表时间：
2016-06-01
期刊：
影响因子：
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通讯作者：
Zhou L
中科院分区：
文献类型：
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作者：
Yao Y;Ye H;Qi Z;Mo L;Yue Q;Baral A;Hoon DSB;Vera JC;Heiss JD;Chen CC;Zhang J;Jin K;Wang Y;Zang X;Mao Y;Zhou L
本研究旨在探讨B7家族成员B7-H4（B7 x/B7 S1）在胶质瘤中的临床意义及其免疫抑制机制。比较不同级别胶质瘤患者脑组织/脑脊液中B7-H4水平。用Kaplan-Meier分析生存数据以确定B7-H4的预后价值。用流式细胞仪、中和抗体和transwell趋化实验研究了CD 133+细胞分泌的细胞因子对人Mφ表达B7-H4的刺激作用。利用shRNA、报告载体和ChIP检测STAT 3与B7-H4启动子的结合。通过吞噬功能、T细胞增殖/凋亡和细胞因子的产生来评价B7-H4+ Mφs在体外的功能，并在异种移植模型中进行体内分析。我们发现B7-H4在肿瘤中的表达与人胶质母细胞瘤的预后相关，并与恶性程度直接相关。从机制上讲，胶质瘤启动CD 133+细胞和巨噬细胞/小胶质细胞共相互作用通过肿瘤细胞和微环境支持细胞中的IL-6和IL-10激活B7-H4的表达。IL-6激活的STAT 3与B7-H4基因启动子结合，增强B7-H4基因的表达。此外，CD 133+细胞通过沉默巨噬细胞/小胶质细胞上的B7-H4表达介导免疫抑制，这导致异种移植胶质瘤小鼠模型中微环境T细胞功能增加和肿瘤消退。我们已经确定了B7-H4激活的巨噬细胞/小胶质细胞在神经胶质瘤的微环境中作为一个重要的免疫抑制事件阻断有效的T细胞免疫反应。
The objective of this study was to evaluate clinical significance and immunosuppressive mechanisms of B7-H4 (B7x/B7S1), a B7 family member, in glioma. B7-H4 levels in glioma tissue/cerebral spinal fluid (CSF) were compared between different grades of glioma patients. Survival data were analyzed with Kaplan–Meier to determine prognostic value of B7-H4. Cytokines from CD133+ cells to stimulate the expression of B7-H4 on human Mφs were investigated by FACS, neutralizing antibodies and transwell chemotaxis assay. shRNA, reporter vector and ChIP were used to determine the binding of STAT3 to the B7-H4 promoter. The function of B7-H4+ Mφs in vitro was evaluated through phagocytosis, T cell proliferation/apoptosis and cytokine production as well as in xenografted model for in vivo analysis. We found that B7-H4 expression in tumors was associated with prognosis of human glioblastoma and correlated directly with malignant grades. Mechanistically, glioma initiating CD133+ cells and macrophages/microglia co-interaction activated expression of B7-H4 via IL-6 and IL-10 in both tumor cells and microenvironment supporting cells. IL-6-activated STAT3 bound to the promoter of B7-H4 gene and enhanced B7-H4 expression. Furthermore, CD133+ cells mediated immunosuppression through B7-H4 expression on macrophages/microglia by silencing of B7-H4 expression on these cells which led to increased microenvironment T cell function and tumor regression in the xenograft glioma mouse model. We have identified B7-H4 activation on macrophages/microglia in the microenvironment of gliomas as an important immunosuppressive event blocking effective T-cell immune responses.