title: 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.
abstract: The objective of this study was to evaluate clinical significance and immunosuppressive mechanisms of B7-H4 (B7x/B7S1), a B7 family member, in glioma.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.|Department of Neurosurgery, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R China.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Ye
authors.affiliation: Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Zengxin
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Department of Neurosurgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
authors.forename: Lianjie
authors.initials: L
authors.lastname: Mo
authors.affiliation: Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yue
authors.affiliation: Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 437001, China.
authors.forename: Aparajita
authors.initials: A
authors.lastname: Baral
authors.affiliation: Dept Molecular Oncology, John Wayne Cancer Institute, Santa Monica, Ca 90404, USA.
authors.forename: Dave S B
authors.initials: DSB
authors.lastname: Hoon
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, 10/3D20, MSC-1414, Bethesda, Maryland 20892-1414, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Vera
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, 10/3D20, MSC-1414, Bethesda, Maryland 20892-1414, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Heiss
authors.affiliation: Center for Theoretic and Applied Oncology, University of California, San Diego, CA 92093, USA.
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
authors.affiliation: School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of North Texas Health Science Center, Fort Worth, TX76107, USA.
authors.forename: Kunlin
authors.initials: K
authors.lastname: Jin
authors.affiliation: Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY 10461, USA.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.|Department of Neurosurgery, Shanghai Medical College, Fudan University, Shanghai 200032, China.|State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.|Department of Neurosurgery, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Liangfu
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D053612:Janus Kinases / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009928:Organ Specificity; D011379:Prognosis; D012189:Retrospective Studies; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000502:physiology*; D055815:Young Adult
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; D053612:Janus Kinases