title: The blockage of Notch signalling promoted the generation of polymorphonuclear myeloid-derived suppressor cells with lower immunosuppression.
abstract: Myeloid-derived suppressor cells (MDSCs) mostly consisting of polymorphonuclear (PMN)-MDSCs and mononuclear MDSCs have been considered to play critical roles in immunosuppression, angiogenesis, invasion and metastases of various tumours. However, it is still unclear the regulated mechanisms underlying the generation and immunosuppression of two major MDSC subsets. Here, we report Notch signalling was inhibited significantly in tumour-bearing mouse MDSCs, in which PMN-MDSCs were the major population. MDSCs without recombination signal binding protein-Jк (RBP-J), the critical transcription factor mediating signalling from all four mammalian Notch receptors, reduced their ability of inhibiting the proliferation and activation of allogenic T cells. RBP-J-deficient MDSCs could not down-regulate the expression of co-stimulation molecules on dendritic cells (DCs). The antigen presentation capacity of DCs co-cultured with RBP-J-deficient MDSCs was not impaired in contrast to controls. Moreover, we show the blockage of Notch signalling could improve the generation of PMN-MDSCs but inhibit the production of mononuclear MDSCs both in vitro and in vivo. Stat3 pathway was suppressed in MDSCs blocked Notch signalling and Stat3 activation by IL-6 could reverse the phenotype and immunosuppression of Notch signalling-deficient MDSCs. Therefore, targeting Notch signalling may be an effective therapeutic strategy in tumour therapy.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China.
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Wang
authors.affiliation: Department of Pathology, Liaocheng People's Hospital, Liaocheng, 252000, Shandong Province, PR China.
authors.forename: Qing-Yang
authors.initials: QY
authors.lastname: Lu
authors.affiliation: Department of Oncology, Shaanxi Province Cancer Hospital, Xi'an, 710061, Shaanxi Province, PR China.
authors.forename: Ya-Huan
authors.initials: YH
authors.lastname: Guo
authors.affiliation: Department of Oncology, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, 710001, Shaanxi Province, PR China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Song
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China. Electronic address: peijun1020@163.com.
authors.forename: Pei-Jun
authors.initials: PJ
authors.lastname: Liu
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China. Electronic address: tanking@sina.com.
authors.forename: Yao-Chun
authors.initials: YC
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017951:Antigen Presentation; D001853:Bone Marrow; D002135:Calcium-Binding Proteins; D003713:Dendritic Cells; D007108:Immune Tolerance; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000276:immunology*; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D000072100:Jagged-1 Protein / Q000276:immunology; D000072101:Jagged-2 Protein / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D010529:Peritoneal Cavity / Q000166:cytology; D034741:RNA, Small Interfering; D051880:Receptors, Notch / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; C512925:Dlk1 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; C490503:Jag2 protein, mouse; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
keywords: Development; Immunosuppression; MDSCs; Notch signalling; Stat3 pathway