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

Qirui Wang, Zhenqiang He, Menggui Huang, Tianrun Liu, Yanling Wang, Haineng Xu, Hao Duan, Peihong Ma, Lin Zhang, Scott S. Zamvil, Juan Hidalgo, Zhenfeng Zhang, Donald M. O’Rourke, Nadia Dahmane, Steven Brem, Yonggao Mou, Yanqing Gong and Yi Fan ()
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Qirui Wang: University of Pennsylvania Perelman School of Medicine
Zhenqiang He: University of Pennsylvania Perelman School of Medicine
Menggui Huang: University of Pennsylvania Perelman School of Medicine
Tianrun Liu: University of Pennsylvania Perelman School of Medicine
Yanling Wang: University of Pennsylvania Perelman School of Medicine
Haineng Xu: University of Pennsylvania Perelman School of Medicine
Hao Duan: University of Pennsylvania Perelman School of Medicine
Peihong Ma: University of Pennsylvania Perelman School of Medicine
Lin Zhang: University of Pennsylvania Perelman School of Medicine
Scott S. Zamvil: University of California at San Francisco
Juan Hidalgo: Autonomous University of Barcelona
Zhenfeng Zhang: Second Affiliated Hospital of Guangzhou Medical University
Donald M. O’Rourke: University of Pennsylvania Perelman School of Medicine
Nadia Dahmane: University of Pennsylvania Perelman School of Medicine
Steven Brem: University of Pennsylvania Perelman School of Medicine
Yonggao Mou: Sun Yat-sen University Cancer Center
Yanqing Gong: University of Pennsylvania Perelman School of Medicine
Yi Fan: University of Pennsylvania Perelman School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03050-0

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