Reprogramming the immunosuppressive microenvironment of IDH1 wild-type glioblastoma by blocking Wnt signaling between microglia and cancer cells.
Reprogramming the immunosuppressive microenvironment of IDH1 wild-type glioblastoma by blocking Wnt signaling between microglia and cancer cells.
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通过阻断小胶质细胞和癌细胞之间的 Wnt 信号传导重新编程 IDH1 野生型胶质母细胞瘤的免疫抑制微环境
DOI：
10.1080/2162402x.2021.1932061
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发表时间：
2021-06-06
期刊：
影响因子：
7.2
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Fan D;Yue Q;Chen J;Wang C;Yu R;Jin Z;Yin S;Wang Q;Chen L;Liao X;Peng C;Zhang J;Cao Z;Mao Y;Huang R;Chen L;Li C
绝大多数（>90%）胶质母细胞瘤（GBM）患者属于异柠檬酸脱氢酶1野生型（IDH 1 WT）组，其预后不良，中位生存期小于15个月。本研究使用中国胶质瘤基因组图谱（CGGA）数据库，证实了206例IDH 1 WT胶质瘤患者中许多免疫抑制基因以及Wnt/β-catenin信号转导的关键基因β-catenin基因上调。在IDH 1 WT GBM患者和IDH 1 WT GL 261胶质瘤同种异体移植物中进一步证实了具有免疫抑制表型的小胶质细胞的增加和β-连环蛋白蛋白的过表达。随后，我们发现IDH 1 WT GL 261细胞来源的条件培养基激活了原代小胶质细胞中的Wnt/β-连环蛋白信号传导，并触发了它们向免疫抑制表型的转变。阻断Wnt/β-连环蛋白信号传导不仅减弱了小胶质细胞向免疫抑制亚型的极化，而且通过同时增强细胞毒性CD 8 + T细胞浸润和下调调节性T细胞，重新激活了IDH 1 WT GBM同种异体移植物中的免疫应答。正电子发射断层扫描成像显示，在阻断Wnt信号传导后，IDH 1 WT GBM同种异体移植物中的促炎活性增强。最后，灌胃给予Wnt信号传导抑制剂显著抑制了肿瘤增殖并改善了携带IDH 1 WT GBM同种异体移植物的模型小鼠的存活率。CD 8 + T细胞的消耗显著地消除了由Wnt信号传导抑制剂诱导的治疗功效。总之，目前的工作表明IDH 1 WT胶质瘤细胞和免疫抑制性小胶质细胞之间的串扰在维持免疫抑制性胶质瘤微环境中是重要的。阻断Wnt/β-连环蛋白信号传导是通过改善不利的免疫抑制微环境来对IDH 1 WT GBM治疗的有希望的补充。
ABSTRACT The vast majority (>90%) of glioblastoma (GBM) patients belong to the isocitrate dehydrogenase 1 wild type (IDH1WT) group which exhibits a poor prognosis with a median survival of less than 15 months. This study demonstrated numerous immunosuppressive genes as well as β-catenin gene, pivotal for Wnt/β-catenin signaling, were upregulated in 206 IDH1WT glioma patients using the Chinese Glioma Genome Atlas (CGGA) database. The increase in microglia with an immunosuppressive phenotype and the overexpression of β-catenin protein were further verified in IDH1WT GBM patients and IDH1WT GL261 glioma allografts. Subsequently, we found that IDH1WT GL261 cell-derived conditioned medium activated Wnt/β-catenin signaling in primary microglia and triggered their transition to an immunosuppressive phenotype. Blocking Wnt/β-catenin signaling not only attenuated microglial polarization to the immunosuppressive subtype but also reactivated immune responses in IDH1WT GBM allografts by simultaneously enhancing cytotoxic CD8+ T cell infiltration and downregulating regulatory T cells. Positron emission tomography imaging demonstrated enhanced proinflammatory activities in IDH1WT GBM allografts after the blockade of Wnt signaling. Finally, gavage administration of a Wnt signaling inhibitor significantly restrained tumor proliferation and improved the survival of model mice bearing IDH1WT GBM allografts. Depletion of CD8+ T cells remarkably abrogated the therapeutic efficacy induced by the Wnt signaling inhibitor. Overall, the present work indicates that the crosstalk between IDH1WT glioma cells and immunosuppressive microglia is important in maintaining the immunosuppressive glioma microenvironment. Blocking Wnt/β-catenin signaling is a promising complement for IDH1WT GBM treatment by improving the hostile immunosuppressive microenvironment.