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Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α.

  • Author(s): Wang, Qirui
  • He, Zhenqiang
  • Huang, Menggui
  • Liu, Tianrun
  • Wang, Yanling
  • Xu, Haineng
  • Duan, Hao
  • Ma, Peihong
  • Zhang, Lin
  • Zamvil, Scott S
  • Hidalgo, Juan
  • Zhang, Zhenfeng
  • O'Rourke, Donald M
  • Dahmane, Nadia
  • Brem, Steven
  • Mou, Yonggao
  • Gong, Yanqing
  • Fan, Yi
  • et al.
Abstract

Spatiotemporal regulation of tumor immunity remains largely unexplored. Here we identify a vascular niche that controls alternative macrophage activation in glioblastoma (GBM). We show that tumor-promoting macrophages are spatially proximate to GBM-associated endothelial cells (ECs), permissive for angiocrine-induced macrophage polarization. We identify ECs as one of the major sources for interleukin-6 (IL-6) expression in GBM microenvironment. Furthermore, we reveal that colony-stimulating factor-1 and angiocrine IL-6 induce robust arginase-1 expression and macrophage alternative activation, mediated through peroxisome proliferator-activated receptor-γ-dependent transcriptional activation of hypoxia-inducible factor-2α. Finally, utilizing a genetic murine GBM model, we show that EC-specific knockout of IL-6 inhibits macrophage alternative activation and improves survival in the GBM-bearing mice. These findings illustrate a vascular niche-dependent mechanism for alternative macrophage activation and cancer progression, and suggest that targeting endothelial IL-6 may offer a selective and efficient therapeutic strategy for GBM, and possibly other solid malignant tumors.

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