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Nat Commun. 2018 Feb 8;9(1):559. doi: 10.1038/s41467-018-03050-0.

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

Author information

1
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
2
School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, China.
3
Department of Neurosurgery, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
4
Department of Otorhinolaryngology, Division of Head and Neck Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China.
5
Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
6
Department of Neurology and Program in Immunology, University of California at San Francisco, San Francisco, CA, 94158, USA.
7
Department of Cellular Biology, Physiology, and Immunology, Autonomous University of Barcelona, 08193, Barcelona, Spain.
8
Department of Radiology The, Second Affiliated Hospital of Guangzhou Medical University, 510260, Guangzhou, China.
9
Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
10
Department of Medicine, Division of Human Genetics and Translational Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
11
Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. fanyi@uphs.upenn.edu.
12
Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. fanyi@uphs.upenn.edu.

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.

PMID:
29422647
PMCID:
PMC5805734
DOI:
10.1038/s41467-018-03050-0
[Indexed for MEDLINE]
Free PMC Article

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