Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α
Wang, Qirui (Southern Medical University. School of Traditional Chinese Medicine)
He, Zhenqiang (Sun Yat-sen University Cancer Center. Department of Neurosurgery)
Huang, Menggui (University of Pennsylvania Perelman School of Medicine. Department of Radiation Oncology)
Liu, Tianrun (The Sixth Affiliated Hospital of Sun Yat-sen University. Department of Otorhinolaryngology)
Wang, Yanling (University of Pennsylvania Perelman School of Medicine. Department of Radiation Oncology)
Xu, Haineng (University of Pennsylvania Perelman School of Medicine. Department of Radiation Oncology)
Duan, Hao (Sun Yat-sen University Cancer Center. Department of Neurosurgery)
Ma, Peihong (University of Pennsylvania Perelman School of Medicine. Department of Radiation Oncology)
Zhang, Lin (University of Pennsylvania Perelman School of Medicine. Department of Obstetrics and Gynecology)
Zamvil, Scott S. (University of California at San Francisco. Department of Neurology and Program in Immunology)
Hidalgo Pareja, Juan (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Zhang, Zhenfeng (Second Affiliated Hospital of Guangzhou Medical University. Department of Radiology The)
O'Rourke, Donald M. (University of Pennsylvania Perelman School of Medicine. Department of Neurosurgery)
Dahmane, Nadia (University of Pennsylvania Perelman School of Medicine. Department of Neurosurgery)
Brem, Steven (University of Pennsylvania Perelman School of Medicine. Department of Neurosurgery)
Mou, Yonggao (Sun Yat-sen University Cancer Center. Department of Neurosurgery)
Gong, Yanqing (University of Pennsylvania Perelman School of Medicine. Department of Medicine)
Fan, Yi (University of Pennsylvania Perelman School of Medicine. Department of Neurosurgery)

Data:	2018
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad SAF2011-23272 Ministerio de Economía y Competitividad SAF2014-56546-R
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Nature communications, Vol. 9 (February 2018) , art. 559, ISSN 2041-1723

DOI: 10.1038/s41467-018-03050-0
PMID: 29422647

15 p, 3.7 MB

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