文章目录

色氨酸代谢驱动idh突变胶质瘤的动态免疫抑制髓系状态

原文发布日期：2021-05-24

英文摘要：

摘要翻译：

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文章：

色氨酸代谢驱动idh突变胶质瘤的动态免疫抑制髓系状态

Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas

原文发布日期：2021-05-24

英文摘要：

The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.

摘要翻译：

在肿瘤进展过程中内含母细胞的动力学和表型不为人们所了解。在这里，我们使用纵向单细胞定位技术来定义胶质母细胞瘤中的髓系细胞状态，并展示了这些状态受到肿瘤基因型严格控制。在是ocitrate脱氢酶（IDH）突变瘤中，内侵性髓系细胞的分化被阻止，导致不成熟表型。在晚期胶质母细胞瘤中，由单核细胞分化而来的巨噬细胞推动微环境中发生容耐导向，从而阻碍了T细胞的应答。我们定义了由内侵巨噬细胞推动的 IDH 依赖性肿瘤教育，并将其与 tryptophan代谢的复杂重组因果相关联，从而激活了 aryl 氢化物受体。我们进一步显示，IDH突变导致肿瘤代谢的变化维持了这一轴在旁路细胞中，并且 pharmacological 摘除 tryptophan 的代谢能够逆转免疫抑制。总结来说，我们提供了证据表明胶质母细胞基因型决定肿瘤内的一个由驻留和内侵髓系细胞组成的网络，并将 tryptophan 代谢识别为针对 IDH 突变瘤免疫治疗的目标。