The R132H mutation in IDH1 promotes the recruitment of NK cells through CX3CL1/CX3CR1 chemotaxis and is correlated with a better prognosis in gliomas
The R132H mutation in IDH1 promotes the recruitment of NK cells through CX3CL1/CX3CR1 chemotaxis and is correlated with a better prognosis in gliomas
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DOI：
10.1111/imcb.12225
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发表时间：
2019-05
影响因子：
4
通讯作者：
Feifei Ren;Qitai Zhao;Lan Huang;Yujia Zheng;Lifeng Li;Qianyi He;Chaoqi Zhang;Feng Li;N. R. Maimela;Zhi Sun;Qing‐quan Jia;Y. Ping;Zhen Zhang;Xinfeng Chen;Ying Yue;Shasha Liu;Ling Cao;Yi Zhang
中科院分区：
文献类型：
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作者：
Feifei Ren;Qitai Zhao;Lan Huang;Yujia Zheng;Lifeng Li;Qianyi He;Chaoqi Zhang;Feng Li;N. R. Maimela;Zhi Sun;Qing‐quan Jia;Y. Ping;Zhen Zhang;Xinfeng Chen;Ying Yue;Shasha Liu;Ling Cao;Yi Zhang
异柠檬酸脱氢酶（IDH）1基因突变，特别是R132 H突变，已被报道与胶质瘤患者的预后较好。然而，其潜在的分子机制尚未得到很好的理解。许多因素可能导致IDH 1野生型和IDH 1突变型神经胶质瘤患者的生存差异，其中免疫成分发挥着潜在的重要作用。在这项研究中，我们分析了癌症基因组图谱（TCGA）和中国胶质瘤基因组图谱（CGGA）数据库，以及胶质瘤患者来源的肿瘤样本。我们发现IDH 1突变型胶质瘤患者中有较高的自然杀伤（NK）细胞浸润，这与较好的预后相关。我们还发现IDH 1-R132肿瘤细胞具有更高的趋化因子CX 3CL 1表达水平。这是由于IDH 1突变体将α-酮戊二酸转化为R（-）-2-羟基戊二酸以及核因子κ B的磷酸化所致。CX 3CL 1的敲低降低了NK细胞的迁移。此外，在TCGA和CGGA数据库以及临床样本中，CX 3CL 1的高水平表达与胶质瘤患者的存活率呈正相关。总的来说，我们的数据已经确定了一种新的机制，其中IDH 1基因的R132 H突变通过促进NK细胞通过CX 3CL 1/CX 3CR 1趋化性的募集而作为肿瘤抑制因子。
Mutations in the isocitrate dehydrogenase (IDH) 1 gene, especially the R132H mutation, have been reported to be associated with a better prognosis in glioma patients. However, the underlying molecular mechanisms are not yet well understood. Many factors may contribute to differences in the survival of IDH1 wild‐type and IDH1 mutant glioma patients, in which immune components play a potentially important role. In this study, we analyzed The Cancer Genome Atlas (TCGA), and the Chinese Glioma Genome Atlas (CGGA) databases, as well as glioma patient‐derived tumor samples. We found that there was a higher infiltration of natural killer (NK) cells in IDH1 mutant glioma patients, and this was correlated with a better prognosis. We also showed that IDH1‐R132 tumor cells had higher expression levels of the chemokine CX3CL1. This arises as a result of the conversion of α‐ketoglutarate to R(‐)‐2‐hydroxyglutarate by the IDH1 mutant and the resultant phosphorylation of nuclear factor kappa B. Knockdown of CX3CL1 decreased the migration of NK cells. In addition, the high levels of expression of CX3CL1 were positively correlated with glioma patient survival in the TCGA and CGGA databases, and in the clinical samples. Overall, our data have identified a novel mechanism in which R132H mutation of the IDH1 gene serves as a tumor suppressor by promoting the recruitment of NK cells through CX3CL1/CX3CR1 chemotaxis.