Abstract：
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.
摘要：
单核细胞衍生的肿瘤相关巨噬细胞（Mo-TAMs）强烈浸润弥漫性神经胶质瘤，具有显着的异质性。使用单细胞转录组学，我们绘制了51例异柠檬酸脱氢酶(IDH)野生型胶质母细胞瘤或IDH突变型胶质瘤患者Mo-TAM的空间分辨转录图.我们表征了Mo-TAM子集，该子集位于坏死周围的生态位，并因缺氧生态位线索而偏斜，以获得缺氧反应特征。缺氧-TAM通过激活肾上腺髓质素旁分泌信号使内皮粘附连接不稳定,从而刺激高渗透的新血管系统，从而阻碍成胶质细胞瘤异种移植物中的药物递送。因此，低氧-TAM产生的肾上腺髓质素的遗传消融或药物阻断可恢复血管完整性，提高抗肿瘤剂dabrafenib的肿瘤内浓度，并实现组合治疗益处。缺氧-TAM或肾上腺髓质素表达的比例增加预示着肿瘤血管通透性过高和胶质母细胞瘤的预后较差。我们的发现强调了弥漫性神经胶质瘤中Mo-TAM的多样性和空间生态位引导的Mo-TAM重编程，并指出了针对低氧-TAM的潜在治疗方法使肿瘤血管正常化。
