Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Amy Medical University), and The Key Laboratory of Tumor Immunopathology, The Ministry of Education of China, Chongqing 400038, P.R. China.
Department of Neurosurgery and Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China.
Cancer Cell. 2024 May 13;42(5):815-832.e12. doi: 10.1016/j.ccell.2024.03.013. Epub 2024 Apr 18.
Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.
单核细胞衍生的肿瘤相关巨噬细胞（Mo-TAMs）在弥漫性神经胶质瘤中浸润程度很高，且具有显著的异质性。通过单细胞转录组学，我们描绘了 51 名异柠檬酸脱氢酶（IDH）野生型胶质母细胞瘤或 IDH 突变型胶质瘤患者的 Mo-TAMs 的空间分辨转录图谱。我们鉴定了一个 Mo-TAM 亚群，该亚群定位于坏死周围龛位，并受缺氧龛位线索的影响，获得了缺氧反应特征。缺氧-TAM 通过激活肾上腺髓质素旁分泌信号来破坏内皮细胞黏附连接，从而刺激通透性增加的新生血管，这会阻碍胶质母细胞瘤异种移植物中的药物递送。因此，通过遗传消融或药理学阻断缺氧-TAM 产生的肾上腺髓质素可以恢复血管完整性，提高抗肿瘤药物 dabrafenib 在肿瘤内的浓度，并实现联合治疗的益处。增加 Hypoxia-TAM 或肾上腺髓质素表达的比例可预测肿瘤血管通透性增加和胶质母细胞瘤预后不良。我们的研究结果强调了弥漫性神经胶质瘤中 Mo-TAM 的多样性和空间龛位驱动的 Mo-TAM 重编程，并指出了针对 Hypoxia-TAM 的潜在治疗方法，以实现肿瘤血管的正常化。
