title: CD14(+)S100A9(+) monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer.
abstract: BACKGROUND
  Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T-cell immunity in tumor-bearing hosts. Their clinical relevance remains unclear.
  
  
  OBJECTIVE
  To identify subtypes of myeloid-derived suppressor cells in patients with non-small cell lung cancer (NSCLC) and their clinical relevance.
  
  
  METHODS
  CD11b(+)CD14(-) and CD11b(+)CD14(+) cells, determined and phenotyped by fluorescence-activated cell sorter analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naive patients with advanced NSCLC were correlated with clinical data. T-cell activation in response to CD3/CD28 costimulation was determined by carboxy-fluorescein diacetate succinimidyl ester (CFSE) staining and ELISA analysis of IFN-γ. The percentage of CD11b(+)CD14(+)S100A9(+) cells in PBMCs was correlated with and tested as a predictor for treatment response in a cohort of patients prospectively receiving first-line cisplatin-based chemotherapy.
  
  
  RESULTS
  Patients with NSCLC had a significantly higher ratio of CD11b(+)CD14(+) cells than healthy subjects, which was correlated with poor performance status and poor response to chemotherapy. The depletion of these cells in the PBMC reversed the suppression of CD8(+) and CD4(+) T cells. Isolated CD11b(+)CD14(+) cells suppressed CD8(+) T-cell proliferation and IFN-γ production, and the former effect was attenuated by the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine hydrochloride, arginase inhibitor N-hydroxy-nor-l-arginine (nor-NOHA), and blocking antibodies for IL-4Rα(+) and IL-10. CD11b(+)CD14(+) cells were monocyte-like, expressing CD33(+), CD15(-/low), IL-4Rα(+), and S100A9(+) and producing iNOS, arginase, and several cytokines. The ratio of S100A9(+) cells positively correlated with the suppressive ability of the CD11b(+)CD14(+) cells, was associated with poor response to chemotherapy, and predicted shorter progression-free survival.
  
  
  CONCLUSIONS
  CD14(+)S100A9(+) inflammatory monocytes in patients with NSCLC are a distinct subset of MDSCs, which suppress T cells by arginase, iNOS, and the IL-13/IL-4Rα axis. The amount of these inflammatory monocytes is associated with poor response to chemotherapy. Clinical trial registered with www.clinicaltrials.gov (NCT 01204307).
authors.affiliation: Pulmonary Research Center, Chang Gung Medical Foundation, Chang Gung University, 199, Tun-Hwa North Road, Taipei, Taiwan.
authors.forename: Po-Hao
authors.initials: PH
authors.lastname: Feng
authors.forename: Kang-Yun
authors.initials: KY
authors.lastname: Lee
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chang
authors.forename: Yao-Fei
authors.initials: YF
authors.lastname: Chan
authors.forename: Lu-Wei
authors.initials: LW
authors.lastname: Kuo
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Lin
authors.forename: Fu-Tsai
authors.initials: FT
authors.lastname: Chung
authors.forename: Chih-Shi
authors.initials: CS
authors.lastname: Kuo
authors.forename: Chih-Teng
authors.initials: CT
authors.lastname: Yu
authors.forename: Shu-Min
authors.initials: SM
authors.lastname: Lin
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Wang
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chou
authors.forename: Chien-Da
authors.initials: CD
authors.lastname: Huang
authors.forename: Han-Pin
authors.initials: HP
authors.lastname: Kuo
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001119:Arginase / Q000378:metabolism; D039481:CD11b Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D040502:Calgranulin B / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000276:immunology*; D049109:Cell Proliferation; D002945:Cisplatin / Q000627:therapeutic use; D018920:Coculture Techniques; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D018793:Interleukin-13 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000032:analysis*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress; D019948:Receptors, Interleukin-4 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D039481:CD11b Antigen; D040502:Calgranulin B; D018793:Interleukin-13; D018950:Lipopolysaccharide Receptors; D019948:Receptors, Interleukin-4; D052247:Nitric Oxide Synthase Type II; D001119:Arginase; D002945:Cisplatin