Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.

Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.
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DOI:
10.1016/j.ccell.2017.06.003
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发表时间:
2017-07-10
期刊:
影响因子:
50.3
通讯作者:
Verhaak RGW
Verhaak RGW
中科院分区:
医学1区
文献类型:
--
作者:
Wang Q;Hu B;Hu X;Kim H;Squatrito M;Scarpace L;deCarvalho AC;Lyu S;Li P;Li Y;Barthel F;Cho HJ;Lin YH;Satani N;Martinez-Ledesma E;Zheng S;Chang E;Sauvé CG;Olar A;Lan ZD;Finocchiaro G;Phillips JJ;Berger MS;Gabrusiewicz KR;Wang G;Eskilsson E;Hu J;Mikkelsen T;DePinho RA;Muller F;Heimberger AB;Sulman EP;Nam DH;Verhaak RGW

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我们利用IDH野生型胶质母细胞瘤、衍生神经球和单细胞基因表达谱来定义三种肿瘤内在转录亚型,分别命名为原神经、间充质和经典。转录组亚型多样性与肿瘤内异质性增加和肿瘤微环境的存在相关。计算机细胞分选鉴定了胶质瘤微环境中的巨噬细胞/小胶质细胞、CD 4 + T淋巴细胞和中性粒细胞。NF 1缺乏导致肿瘤相关巨噬细胞/小胶质细胞浸润增加。纵向转录组分析显示,在55%的病例中保留了表达亚型。基于基因特征的肿瘤微环境推断显示,疾病复发后,侵袭性单核细胞减少,巨噬细胞/小胶质细胞亚型依赖性增加。诊断时或复发时的高突变与CD 8 + T细胞富集相关。M2巨噬细胞检测频率与放疗后短期复发相关Wang等人定义了三种IDH野生型胶质母细胞瘤内在基因表达亚型,它们部分由肿瘤免疫环境形成。NF 1缺乏导致巨噬细胞/小胶质细胞浸润增加。比较匹配的原发性和复发性肿瘤揭示了频繁的表达亚型变化。
We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4+ T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8+ T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy. Wang et al. define three IDH wild-type glioblastoma-intrinsic gene expression subtypes, which are partly shaped by the tumor immune environment. NF1 deficiency results in increased macrophage/microglia infiltration. Comparison of matched primary and recurrent tumors reveals frequent expression subtype changes.
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