The mesenchymal subtype of glioblastoma (GBM) cells characterized by aggressive invasion and therapeutic resistance is thought to be dependent on cell-intrinsic alteration and extrinsic cellular crosstalk. Tumor-associated macrophages (TAMs) are pivotal in tumor progression, chemo-resistance, angiogenesis, and stemness maintenance. However, the impact of TAMs on the shifts in glioma stem cells (GSCs) states remains largely uncovered. Herein, we showed that the triggering receptor expressed on myeloid cells-1 (TREM1) preferentially expressed by M2-like TAMs and induced GSCs into mesenchymal-like states by modulating the secretion of TGFβ2, which activated the TGFβR/SMAD2/3 signaling in GSCs. Furthermore, we demonstrated that TREM1 was transcriptionally regulated by HIF1a under the hypoxic environment and thus promoted an immunosuppressive type of TAMs via activating the TLR2/AKT/mTOR/c-MYC axis. Collectively, this study reveals that cellular communication between TAMs and GSCs through the TREM1-mediated TGFβ2/TGFβR axis is involved in the mesenchymal-like transitions of GSCs. Our study provides valuable insights into the regulatory mechanisms between the tumor immune microenvironment and the malignant characteristics of GBM, which can lead to potential novel strategies targeting TAMs for tumor control.

中文翻译：

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缺氧诱导的 TREM1 通过选择性激活肿瘤相关巨噬细胞促进神经胶质瘤干细胞的间充质样状态

胶质母细胞瘤（GBM）细胞的间充质亚型以侵袭性侵袭和治疗抵抗为特征，被认为依赖于细胞内在的改变和外在的细胞串扰。肿瘤相关巨噬细胞（TAM）在肿瘤进展、化疗耐药、血管生成和干性维持中发挥着关键作用。然而，TAM 对神经胶质瘤干细胞 (GSC) 状态变化的影响仍然很大程度上未被揭示。在此，我们发现表达于骨髓细胞-1（TREM1）上的触发受体优先由M2样TAM表达，并通过调节TGFβ2的分泌诱导GSC进入间充质样状态，从而激活GSC中的TGFβR/SMAD2/3信号传导。此外，我们证明TREM1在缺氧环境下受到HIF1a的转录调节，从而通过激活TLR2/AKT/mTOR/c-MYC轴促进免疫抑制型TAM。总的来说，这项研究揭示了 TAM 和 GSC 之间通过 TREM1 介导的 TGFβ2/TGFβR 轴进行的细胞通讯参与了 GSC 的间质样转变。我们的研究为肿瘤免疫微环境与 GBM 恶性特征之间的调节机制提供了有价值的见解，这可能导致针对 TAM 控制肿瘤的潜在新策略。