Tumour‐associated microglia/macrophages (TAM ) are the most numerous non‐neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM ), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM , but little is known about the potential role of this pathway in TAM . Here, we show that GBM ‐initiating cells induce mTOR signalling in the microglia but not bone marrow‐derived macrophages in both in vitro and in vivo GBM mouse models. mTOR ‐dependent regulation of STAT 3 and NF‐κB activity promotes an immunosuppressive microglial phenotype. This hinders effector T‐cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expanded‐potential stem cells (EPSC )‐derived microglia‐like cells are conditioned by syngeneic patient‐derived GBM ‐initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM.

中文翻译：

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小胶质细胞通过 mTOR 介导的肿瘤微环境免疫抑制促进胶质母细胞瘤。


肿瘤相关小胶质细胞/巨噬细胞（TAM）是多形性胶质母细胞瘤（GBM）肿瘤微环境中数量最多的非肿瘤细胞群，多形性胶质母细胞瘤（GBM）是成人最常见的恶性脑肿瘤。 mTOR 通路是细胞存活/增殖的重要调节因子，在 GBM 中表达上调，但对该通路在 TAM 中的潜在作用知之甚少。在这里，我们表明，在体外和体内GBM 小鼠模型中，GBM 起始细胞会诱导小胶质细胞中的 mTOR 信号传导，但不会诱导骨髓来源的巨噬细胞。 mTOR 依赖性调节 STAT 3 和 NF-κB 活性可促进免疫抑制小胶质细胞表型。这阻碍了效应 T 细胞的浸润、增殖和免疫反应，从而导致肿瘤免疫逃避并促进小鼠模型中的肿瘤生长。我们的结果的转化价值在人类 GBM 的整个转录组数据集和一种新颖的体外模型中得到了证明，在该模型中，扩展潜能干细胞 (EPSC) 衍生的小胶质细胞样细胞受到同源患者衍生的 GBM 起始细胞的调节。这些结果提出了一种可能性，即小胶质细胞可能是 mTOR 抑制的主要目标，而不是 GBM 中的内在肿瘤细胞。