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

Po Hao Feng, Kang Yun Lee, Ya Ling Chang, Yao Fei Chan, Lu Wei Kuo, Ting Yu Lin, Fu Tsai Chung, Chih Shi Kuo, Chih Teng Yu, Shu Min Lin, Chun Hua Wang, Chun Liang Chou, Chien Da Huang, Han Pin Kuo

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

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 correlatedwith 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-4Rα1 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).

Original languageEnglish
Pages (from-to)1025-1036
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume186
Issue number10
DOIs
Publication statusPublished - Nov 15 2012
Externally publishedYes

Keywords

  • Cancer immunity
  • Myeloid-derived suppressor cell
  • Non-small cell lung cancer
  • S100A9

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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