B7-H4(B7x)–Mediated Cross-talk between Glioma-Initiating Cells and Macrophages via the IL6/JAK/STAT3 Pathway Lead to Poor Prognosis in Glioma Patients
Yu Yao1,2, Hongxing Ye3, Zengxin Qi4, Lianjie Mo5, Qi Yue4, Aparajita Baral6, Dave S.B. Hoon7,Juan Carlos Vera8, John D. Heiss8, Clark C. Chen9, Wei Hua1,2, Jianmin Zhang10, Kunlin Jin11, Yin Wang12, Xingxing Zang13,*, Ying Mao1,2,14,*, and Liangfu Zhou1,21 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
2 Department of Neurosurgery, Shanghai Medical College, Fudan University, Shanghai, China.3 Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
4 Shanghai Medical College, Fudan University, Shanghai, China.5 Department of Neurosurgery, Sir Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
6 Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.7 Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California.
8 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
9 Center for Theoretic and Applied Oncology, University of California, San Diego, California.
10 School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
11 Department of Pharmacology, University of North Texas Health Science Center, Fort Worth, Texas.
12 Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai, China.
13 Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York.
14 State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai, China.
Y. Mao, Huashan Hospital, Fudan University, 12# Wulumuqi Middle Road, Shanghai 200040, China. Phone: 86-21-52888828; Fax: 86-21-62489191; E-mail: firstname.lastname@example.org; and X. Zang, Albert Einstein College of Medicine, E-mail: email@example.com
Y. Yao, H. Ye, Z. Qi, and L. Mo contributed equally to this article.
Purpose: The objective of this study was to evaluate clinical significance and immunosuppressive mechanisms of B7-H4 (B7x/B7S1), a B7 family member, in glioma.
Experimental Design: B7-H4 levels in glioma tissue/cerebral spinal fluid (CSF) were compared between different grades of glioma patients. Survival data were analyzed with Kaplan–Meier to determine the prognostic value of B7-H4. Cytokines from CD133+ cells to stimulate the expression of B7-H4 on human macrophages (Mφs) were investigated by FACS, neutralizing antibodies, and Transwell chemotaxis assay. shRNA, reporter vector, and chromatin immunoprecipitation were used to determine the binding of STAT3 to the B7-H4 promoter. The function of B7-H4+ Mφs in vitro was evaluated through phagocytosis, T-cell proliferation/apoptosis, and cytokine production as well as in the xenografted model for in vivo analysis.
Results: We found that B7-H4 expression in tumors was associated with prognosis of human glioblastoma and correlated directly with malignant grades. Mechanistically, glioma initiating CD133+ cells and Mφs/microglia cointeraction activated expression of B7-H4 via IL6 and IL10 in both tumor cells and microenvironment supporting cells. IL6-activated STAT3 bound to the promoter of B7-H4 gene and enhanced B7-H4 expression. Furthermore, CD133+ cells mediated immunosuppression through B7-H4 expression on Mφs/microglia by silencing of B7-H4 expression on these cells, which led to increased microenvironment T-cell function and tumor regression in the xenograft glioma mouse model.
Conclusions: We have identified B7-H4 activation on Mφs/microglia in the microenvironment of gliomas as an important immunosuppressive event blocking effective T-cell immune responses.Clin Cancer Res; 22(11); 2778–90. ©2016 AACR.
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