Mutant IDH1 regulates the tumor-associated immune system in gliomas.
Mutant IDH1 regulates the tumor-associated immune system in gliomas.
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DOI：
10.1101/gad.294991.116
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发表时间：
2017-04-15
影响因子：
10.5
通讯作者：
Holland EC
中科院分区：
文献类型：
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作者：
Amankulor NM;Kim Y;Arora S;Kargl J;Szulzewsky F;Hanke M;Margineantu DH;Rao A;Bolouri H;Delrow J;Hockenbery D;Houghton AM;Holland EC
Amankulor等人创建了突变IDH 1（muIDH 1）和野生型IDH 1（wtIDH 1）神经胶质瘤的同基因配对小鼠模型，并证明IDH 1突变导致白细胞趋化性下调，导致肿瘤相关免疫系统的抑制。含有异柠檬酸脱氢酶1/2（IDH 1/2）突变的胶质瘤具有CpG岛甲基化表型（CIMP），并且患者存活时间比野生型IDH 1/2（wtIDH 1/2）肿瘤显著更长。虽然有许多因素导致这两种肿瘤类型之间的生存差异，但免疫相关的细胞含量差异可能是重要的贡献者。为了研究IDH突变在免疫应答中的作用，我们创建了突变IDH 1（muIDH 1）和wtIDH 1胶质瘤的同基因配对小鼠模型，并证明muIDH 1小鼠与muIDH 1人类胶质瘤显示出许多分子和临床相似性，包括与wtIDH 1相比，2-羟基谷氨酸（2-HG）浓度高100倍，生存时间长，CpG甲基化高。此外，我们发现IDH 1突变导致白细胞趋化性下调，导致肿瘤相关免疫系统的抑制。考虑到免疫细胞如巨噬细胞、小胶质细胞、单核细胞和嗜中性粒细胞的显著浸润与许多癌症类型中的不良预后有关，muIDH 1胶质瘤肿瘤中这些减少的免疫浸润可能部分导致两种胶质瘤类型的侵袭性差异。
Amankulor et al. created a syngeneic pair mouse model for mutant IDH1 (muIDH1) and wild-type IDH1 (wtIDH1) gliomas and demonstrated that IDH1 mutations caused down-regulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system. Gliomas harboring mutations in isocitrate dehydrogenase 1/2 (IDH1/2) have the CpG island methylator phenotype (CIMP) and significantly longer patient survival time than wild-type IDH1/2 (wtIDH1/2) tumors. Although there are many factors underlying the differences in survival between these two tumor types, immune-related differences in cell content are potentially important contributors. In order to investigate the role of IDH mutations in immune response, we created a syngeneic pair mouse model for mutant IDH1 (muIDH1) and wtIDH1 gliomas and demonstrated that muIDH1 mice showed many molecular and clinical similarities to muIDH1 human gliomas, including a 100-fold higher concentration of 2-hydroxygluratate (2-HG), longer survival time, and higher CpG methylation compared with wtIDH1. Also, we showed that IDH1 mutations caused down-regulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system. Given that significant infiltration of immune cells such as macrophages, microglia, monocytes, and neutrophils is linked to poor prognosis in many cancer types, these reduced immune infiltrates in muIDH1 glioma tumors may contribute in part to the differences in aggressiveness of the two glioma types.