Glioblastoma genetic drivers dictate the function of tumor-associated macrophages/microglia and responses to CSF1R inhibition

PDGFB公司 间充质干细胞 小胶质细胞 癌症研究 PDGFRB公司 血管生成 生物 间质细胞 胶质瘤 细胞生物学 化学 肿瘤微环境 免疫学 受体 炎症 生长因子 肿瘤细胞 血小板源性生长因子受体 基因 生物化学
作者
Rohit Rao,Rong Han,Sean Ogurek,Chengbin Xue,Lai Man Natalie Wu,Liguo Zhang,Li Zhang,Jian Hu,Timothy N. Phoenix,Stephen N. Waggoner,Q. Richard Lu
出处
期刊:Neuro-oncology [Oxford University Press]
卷期号:24 (4): 584-597 被引量:41
标识
DOI:10.1093/neuonc/noab228
摘要

Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment (TME) conveys distinct sensitivities to TAM targeting.We generated syngeneic PDGFB- and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in TME cellular compositions and functions in PDGFB- and RAS-driven gliomas.We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas.Our work identifies functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.
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