Microglia/macrophage-derived human CCL18 promotes glioma progression via CCR8-ACP5 axis analyzed in humanized slice model
Yimin Huang, Edyta Motta, Cynthia Nanvuma, Leonard D. Kuhrt, Yuan Yang, Pengfei Xia, Małgorzata Lubas, Shuai Zhu, M Schnauss, Niyeti Qazi, Feng Hu, Huaqiu Zhang, Ting Lei, Michael Synowitz, Charlotte Flüh, Helmut Kettenmann
Abstract
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.