title: Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway.
abstract: Neutrophils are prominent components of solid tumours and exhibit distinct phenotypes in different tumour microenvironments. However, the nature, regulation, function and clinical relevance of neutrophils in human gastric cancer (GC) are presently unknown.
  
  
  
  Flow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from 105 patients with GC. Kaplan-Meier plots for overall survival were performed using the log-rank test. Neutrophils and T cells were isolated, stimulated and/or cultured for in vitro and in vivo regulation and function assays.
  
  
  
  Patients with GC showed a significantly higher neutrophil infiltration in tumours. These tumour-infiltrating neutrophils showed an activated CD54+phenotype and expressed high level immunosuppressive molecule programmed death-ligand 1 (PD-L1). Neutrophils activated by tumours prolonged their lifespan and strongly expressed PD-L1 proteins with similar phenotype to their status in GC, and significant correlations were found between the levels of PD-L1 and CD54 on tumour-infiltrating neutrophils. Moreover, these PD-L1+neutrophils in tumours were associated with disease progression and reduced GC patient survival. Tumour-derived GM-CSF activated neutrophils and induced neutrophil PD-L1 expression via Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signalling pathway. The activated PD-L1+neutrophils effectively suppressed normal T-cell immunity in vitro and contributed to the growth and progression of human GC in vivo; the effect could be reversed by blocking PD-L1 on these neutrophils.
  
  
  
  Our results illuminate a novel mechanism of PD-L1 expression on tumour-activated neutrophils in GC, and also provide functional evidence for these novel GM-CSF-PD-L1 pathways to prevent, and to treat this immune tolerance feature of GC.
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Wang
authors.affiliation: Department of General Surgery and Centre of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yong-Liang
authors.initials: YL
authors.lastname: Zhao
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Liu-Sheng
authors.initials: LS
authors.lastname: Peng
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Chen
authors.affiliation: La Trobe Institute of Molecular Science, School of Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Yi-Pin
authors.initials: YP
authors.lastname: Lv
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Mao
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Jin-Yu
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Teng
authors.affiliation: Department of General Surgery and Centre of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Fu
authors.affiliation: Department of General Surgery and Centre of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Pei-Wu
authors.initials: PW
authors.lastname: Yu
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Guo
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Luo
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Quan-Ming
authors.initials: QM
authors.lastname: Zou
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D053208:Kaplan-Meier Estimate; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018375:Neutrophil Activation; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000276:immunology* / Q000401:mortality; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: GASTRIC CANCER