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

Qirui Wang,Yanqing Gong,Donald M O’Rourke,Peihong Ma,Scott S Zamvil,Juan Hidalgo,Zhenqiang He,Yi Fan,Zhenfeng Zhang,Yonggao Mou,Yanling Wang,Menggui Huang,Nadia Dahmane,Hao Duan,Steven Brem,Tianrun Liu,Lin Zhang,Haineng Xu

doi:10.1038/s41467-018-03050-0

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.

Highlights

Spatiotemporal regulation of tumor immunity remains largely unexplored
Immunofluorescence analysis of surgical tumor specimens from human patients with different grades of gliomas showed that a large population of GBM-associated CD68+ macrophages robustly expressed CD206 and CD163 (Fig. 1a, b) and relatively expressed CD86 at a lower level (Supplementary Fig. 1), while only small population of CD68+ macrophages or microglia cells expressed CD206 in normal brains (Supplementary Fig. 1)
Consistent with previously published work showing that glioma grades correlate with the expression of multiple alternative activation markers in tumor-associated macrophages[23], there was an increase in CD206 expression by tumor-associated macrophages from different grades of gliomas (Fig. 1c), suggesting enhanced alternative activation in these macrophages

Summary

Introduction

Spatiotemporal regulation of tumor immunity remains largely unexplored. Here we identify a vascular niche that controls alternative macrophage activation in glioblastoma (GBM). 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. Growing evidence suggests that alternative macrophage activation is a driving force that fuels cancer progression, but the underlying tumor microenvironment-dependent mechanisms remain largely unknown. We reveal a vascular niche-dependent regulatory system for macrophage activation, targeting which may offer new therapeutic opportunities for the treatment of GBM, and possibly other solid malignant tumors

Methods

Results

Conclusion