Purpose: Mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 have critical diagnostic and prognostic significance in diffuse gliomas. Neomorphic mutant IDH activity has been previously implicated in T-cell suppression; however, the effects of IDH mutations on intratumoral myeloid populations remain underexplored. Here, we investigate the influence of IDH status on the myeloid compartment using human glioma specimens and preclinical models. Experimental Design: We performed RNA-sequencing and quantitative immunofluorescence on newly diagnosed, treatment-naive IDH-mutant grade 4 astrocytoma and IDH-wildtype glioblastoma (GBM) specimens. We also generated a syngeneic murine model, comparing transcriptomic and cell-level changes in paired isogenic glioma lines that differ only in IDH mutational status. Results: Among patient samples, IDH-mutant tumors displayed underrepresentation of suppressive myeloid transcriptional signatures, which was confirmed at the cellular level with decreased numbers of intratumoral M2-like macrophages and MDSCs. Introduction of the IDH-mutant enzyme into murine glioma was sufficient to recapitulate the transcriptomic and cellular shifts observed in patient samples. Conclusions: We provide transcriptomic and cellular evidence that mutant IDH is associated with a quantitative reduction of suppressive myeloid cells in gliomas and that introduction of the mutant enzyme is sufficient to result in corresponding cellular changes using an in vivo preclinical model. These data advance our understanding of high-grade gliomas by identifying key myeloid cell populations that are reprogrammed by mutant-IDH and may be targetable through therapeutic approaches.

中文翻译：

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突变 IDH 调节恶性神经胶质瘤中的抑制性骨髓细胞群


目的：异柠檬酸脱氢酶 (IDH) 基因 IDH1 和 IDH2 的突变对弥漫性胶质瘤具有重要的诊断和预后意义。新形态突变体 IDH 活性先前已被认为与 T 细胞抑制有关。然而，IDH 突变对瘤内骨髓细胞群的影响仍未得到充分研究。在这里，我们使用人类神经胶质瘤标本和临床前模型研究 IDH 状态对骨髓室的影响。实验设计：我们对新诊断的、未经治疗的 IDH 突变 4 级星形细胞瘤和 IDH 野生型胶质母细胞瘤 (GBM) 标本进行了 RNA 测序和定量免疫荧光。我们还生成了同基因小鼠模型，比较了仅 IDH 突变状态不同的配对同基因神经胶质瘤系的转录组和细胞水平变化。结果：在患者样本中，IDH 突变肿瘤表现出抑制性骨髓转录特征的代表性不足，这在细胞水平上得到了证实，瘤内 M2 样巨噬细胞和 MDSC 数量减少。将 IDH 突变酶引入小鼠神经胶质瘤中足以重现在患者样本中观察到的转录组和细胞变化。结论：我们提供了转录组学和细胞学证据，表明突变型 IDH 与神经胶质瘤中抑制性骨髓细胞的数量减少有关，并且使用体内临床前模型，引入突变型酶足以导致相应的细胞变化。这些数据通过识别由突变 IDH 重新编程并可能通过治疗方法靶向的关键骨髓细胞群，增进了我们对高级别神经胶质瘤的理解。