CD14(+)S100A9(+) monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer

Am J Respir Crit Care Med. 2012 Nov 15;186(10):1025-36. doi: 10.1164/rccm.201204-0636OC. Epub 2012 Sep 6.


Rationale: 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.

Objectives: 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.

Measurements and main 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 (NCT 01204307).

Trial registration: NCT01204307.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Arginase / metabolism
  • CD11b Antigen / analysis
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / physiology
  • Calgranulin B / analysis*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / immunology*
  • Cell Proliferation
  • Cisplatin / therapeutic use
  • Coculture Techniques
  • Disease-Free Survival
  • Female
  • Humans
  • Immune Tolerance*
  • Interleukin-13 / metabolism
  • Lipopolysaccharide Receptors / analysis*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology*
  • Male
  • Middle Aged
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Oxidative Stress
  • Receptors, Interleukin-4 / metabolism


  • Antineoplastic Agents
  • CD11b Antigen
  • Calgranulin B
  • Interleukin-13
  • Lipopolysaccharide Receptors
  • Receptors, Interleukin-4
  • Nitric Oxide Synthase Type II
  • Arginase
  • Cisplatin

Associated data