title: Programming of the development of tumor-promoting neutrophils by mesenchymal stromal cells.
abstract: OBJECTIVE
  Neutrophils obtain immunosuppressive function during tumor development, yet the mechanisms are largely unknown. This study explored whether and how mesenchymal stromal cells (MSCs), the key component of tumor microenvironment, regulate the suppressive function of neutrophils.
  
  
  METHODS
  Immunosuppressive function of neutrophils was evaluated by T cell proliferation assay and 4T1 breast tumor model; molecular mechanisms were explored by transcriptional profiling, Real-time RT-PCR, arginase activity assay, and iNOS inhibition experiments.
  
  
  RESULTS
  After being cocultured with MSCs primed by TNF-α (TNF-MSCs), CD11b(+)Ly6G(+) neutrophils isolated from bone marrow of normal mice or spleen of tumor-bearing mice obtained immunosuppressive function to inhibit T cell proliferation in vitro, and to enhance 4T1 tumor progression in vivo. Moreover, arginase activity and expression of iNOS, saa3, some cytokines and chemokines and their receptors, were upregulated in neutrophils after co-culture with TNF-MSCs. Inhibition of iNOS activity attenuated the suppressive effect of TNF-MSC pre-cocultured neutrophils on T cell proliferation.
  
  
  CONCLUSIONS
  MSCs program neutrophils into an immunosuppressive and tumor-promoting phenotype.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences, Tianjin, P.R. China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Hu
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Kui
authors.initials: K
authors.lastname: Dong
authors.forename: Zhina
authors.initials: Z
authors.lastname: Sun
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.forename: Wentian
authors.initials: W
authors.lastname: Liu
authors.forename: Guogang
authors.initials: G
authors.lastname: Xu
authors.forename: Zhongchao
authors.initials: Z
authors.lastname: Han
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Feng
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016130:Immunophenotyping; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D052247:Nitric Oxide Synthase Type II; D001119:Arginase