Factors released from glioma-associated microglia/macrophages (GAMs) play a crucial role in glioblastoma multiforme (GBM) progression. Here, we study the importance of CCL18, a cytokine expressed in human but not in rodent GAMs, as a modulator of glioma growth. Since CCL18 signaling could not be studied in classical mouse glioma models, we developed an approach by transplanting induced pluripotent stem cell-derived human microglia and human glioma cells into mouse brain slices depleted of their intrinsic microglia. We observe that CCL18 promotes glioma cell growth and invasion. Chemokine (C-C motif) receptor 8 (CCR8) is identified as a functional receptor for CCL18 on glioma cells, and ACP5 (acid phosphatase 5) is revealed as an important part of the downstream signaling cascade for mediating glioma growth. We conclude, based on the results from an in vitro, ex vivo humanized glioma model and an in vivo GBM model that microglia/macrophage-derived CCL18 promotes glioma growth.

胶质瘤相关小胶质细胞/巨噬细胞 (GAM) 释放的因子在多形性胶质母细胞瘤 (GBM) 进展中起关键作用。在这里，我们研究了 CCL18（一种在人类中表达但在啮齿动物 GAM 中不表达的细胞因子）作为神经胶质瘤生长调节剂的重要性。由于无法在经典的小鼠神经胶质瘤模型中研究 CCL18 信号传导，我们开发了一种方法，将诱导的多能干细胞衍生的人类小胶质细胞和人类神经胶质瘤细胞移植到耗尽其内在小胶质细胞的小鼠脑切片中。我们观察到 CCL18 促进神经胶质瘤细胞的生长和侵袭。趋化因子（CC 基序）受体 8 (CCR8) 被确定为胶质瘤细胞上 CCL18 的功能性受体，而 ACP5（酸性磷酸酶 5）被揭示为介导胶质瘤生长的下游信号级联反应的重要部分。我们得出结论，体外、离体人源化胶质瘤模型和小胶质细胞/巨噬细胞衍生的 CCL18 促进胶质瘤生长的体内GBM 模型。