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

• Published in: Nature communications Vol. 9; no. 1; pp. 559 - 15
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.02.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 14/5; 45/77; 45/88; 45/90; 631/67/1922; 631/67/327; 64/110; 96/1; Animals; Arginase; Arginase - immunology; Basic Helix-Loop-Helix Transcription Factors - genetics; Brain cancer; Cancer; Cancer therapies; Cell activation; Cell Line, Tumor; Cells, Cultured; Colony-stimulating factor; Cytokines; Disease Progression; Endothelial cells; Endothelial Cells - immunology; Flow cytometry; Glioblastoma; Glioblastoma - immunology; Growth factors; Human subjects; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia-inducible factors; Immunity; Immunology; Interleukin 6; Interleukin-6 - immunology; Macrophage Activation - immunology; Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - immunology; Macrophages; Macrophages - immunology; Medicine; Mice; Microvessels - cytology; Monocytes - immunology; multidisciplinary; Neoplasms, Experimental - immunology; Neurosurgery; Nitric oxide; Otolaryngology; Peroxisome proliferator-activated receptors; Polarization; Polyamines; Radiation; Rodents; Science; Science (multidisciplinary); Survival; Transcription activation; Transcriptional Activation; Tumor Microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03050-0

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. Macrophages in the tumour microenvironment (TME) acquire tumour-promoting functions upon M2 polarization. Here the authors show, in a mouse model of glioblastoma, that endothelial cells in the TME induce macrophage M2 polarization via IL-6 and that depletion of endothelial IL-6 improves survival.