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

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

doi:10.1038/s41467-018-03050-0

Cited by 179 publications

(171 citation statements)

References 69 publications

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“…CGGA: Chinese Glioma Genome Atlas; GBM: glioblastoma; IL: interleukin; OSMR: oncostatin M receptor; RNAseq: RNA sequencing; TCGA: The Cancer Genome Atlas [Color figure can be viewed at wileyonlinelibrary.com] et al De Waele et al, 2018;Lemke et al, 2012;Sharp et al, 2012;Z. Wang et al, 2016;Q. Wang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of oncostatin M receptor regulates local immune response in glioblastoma

Guo

Guan

Cao

et al. 2019

Journal Cellular Physiology

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Glioblastoma (GBM) is the most lethal cancer in central nervous system. It is urgently needed to look for novel therapeutics for GBM. Oncostatin M receptor (OSMR) is a cytokine receptor gene of IL‐6 family and has been reported to be involved in regulating GBM tumorigenesis. However, the role of OSMR regulating the disrupted immune response in GBM need to be further investigated. Three gene expression profiles, Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) data set (GSE16011), were enrolled in our study and used for OSMR expression and survival analysis. The expression of OSMR was further verified with immunohistochemistry and western blot analysis in glioma tissues. Microenvironment cell populations‐counter (MCP‐counter) was applied for analyzing the relationship between OSMR expression and nontumor cells. The functions of OSMR in GBM was investigated by Gene Ontology, Gene set enrichment analysis (GSEA), gene set variation analysis and so on. The analysis of cytokine receptor activity‐related genes in glioma identifies OSMR as a gene with an independent predictive factor for progressive malignancy in GBM. Furthermore, OSMR expression is a prognostic marker in the response prediction to radiotherapy and chemotherapy. OSMR contributes to the regulation of local immune response and extracellular matrix process in GBM. Our findings define an important role of OSMR in the regulation of local immune response in GBM, which may suggest OSMR as a possible biomarker in developing new therapeutic immune strategies in GBM.

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Section: Discussionmentioning

confidence: 99%

Overexpression of oncostatin M receptor regulates local immune response in glioblastoma

Guo

Guan

Cao

et al. 2019

Journal Cellular Physiology

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“…M0 macrophages were polarized into M1 macrophages by further stimulation with LPS and IFN‐γ at 100 ng/mL, or into M2 macrophages by stimulation with IL‐4 at 40 ng/mL and IL‐13 at 20 ng/mL, for 48 hours . After polarization, M2 macrophages were stimulated with poly I:C (25 μg/mL), IFN‐γ (100 ng/mL), TNF‐α (25 ng/mL), IL‐1β (100 ng/mL), IL‐6 (100 ng/mL), or IL‐17A (100 ng/mL) for 6 hours . After stimulation, cells were harvested and subjected to quantitative PCR analysis to measure CD163 and IL‐10 expression.…”

Section: Methodsmentioning

confidence: 99%

Deficiency in interleukin‐10 production by M2 macrophages in eosinophilic chronic rhinosinusitis with nasal polyps

Wang

Yao

Wang

et al. 2018

Int Forum Allergy Rhinol

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Background: M2 macrophages are characterized by high interleukin-10 (IL-10) expression and are critical for resolving inflammation. Although increased accumulation of M2 macrophages has been demonstrated in chronic rhinosinusitis with nasal polyps (CRSwNP), particularly the eosinophilic type, their functional relevance in CRSwNP remains poorly understood.Methods: M1 and M2 macrophages and IL-10 expression in sinonasal tissues were detected by doubleimmunofluorescence staining. THP-1 cells, a human monocytic leukemia cell line, were stimulated with various cytokines to study macrophage polarization and IL-10 expression. Polyp size, computed tomography (CT) scans, and symptom severity were scored.Results: Compared with numbers in control tissues, the numbers of total CD68 + macrophages, interferon regulatory factor 5-positive and CD68 + M1 macrophages, and CD163 + CD68 + and CD206 + CD68 + M2 macrophages were increased in both eosinophilic and non-eosinophilic polyps. However, compared with non-eosinophilic polyps, eosinophilic polyps contained fewer M1 macrophages and more M2 macrophages. Consistent with this, the M1/M2 macrophage ratio was increased in non-eosinophilic polyps, whereas it decreased in eosinophilic polyps. Strikingly, the numbers of IL-10 + CD68 + macrophages and the percentage of IL-10 + CD68 + macrophages relative to the total number of macrophages were decreased in eosinophilic polyps, despite the upregulation of M2 macrophages in this type of polyp. The number of IL-10 + CD68 + M2 macrophages correlated negatively with total symptoms scores, polyp sizes, total CT scores, and the total number of inflammatory cells in patients with eosinophilic CRSwNP. Poly I:C downregulated IL-10 expression in M2 macrophages differentiated from THP-1 cells in vitro.Conclusion: Impaired IL-10 production by M2 macrophages may contribute to sustained inflammation in eosinophilic CRSwNP.vv C 2018 ARS-AAOA, LLC.

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“…Myeloid cells extensively infiltrate tumors and represent the most common nonmalignant cell within the GBM microenvironment (26,27). Immunosuppressive myeloid cells in GBM include alternatively activated (M2) macrophages (28)(29)(30), myeloidderived suppressor cells (MDSC; refs. 23,24,31), and immature monocytes (22,25,32).…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

Lamano

et al. 2019

Clinical Cancer Research

133

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Purpose: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation.Experimental Design: Conditioned media from patientderived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate na€ ve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors.Results: GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8 þ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy.Conclusions: Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM. Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001; ÃÃÃÃ , P < 0.0001.Lamano et al. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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

Cited by 179 publications

References 69 publications

Overexpression of oncostatin M receptor regulates local immune response in glioblastoma

Overexpression of oncostatin M receptor regulates local immune response in glioblastoma

Deficiency in interleukin‐10 production by M2 macrophages in eosinophilic chronic rhinosinusitis with nasal polyps

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

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