Microglia/macrophage-derived human CCL18 promotes glioma progression via CCR8-ACP5 axis analyzed in humanized slice model

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. [Display omitted] •Transplanting iPSC-derived human microglia and glioma cells into murine brain slices•CCL18 expressed by glioma-associated microglia/macrophages promotes glioma cell growth•CCR8 acts as functional receptor for the CCL18-induced tumor-promoting effect•CCL18 promotes glioma progression via ACP5/PRAS40/Akt signaling cascade Huang et al. developed an ex vivo model by transplanting induced pluripotent stem cell (iPSC)-derived human microglia (iMGL) to investigate the effect of human microglia/macrophage-derived CCL18 on glioma cells. They show that CCL18 promotes glioma cell proliferation and migration via ACP5/PRAS40/Akt signaling.