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).
|頁（從 - 到）||1025-1036|
|期刊||American Journal of Respiratory and Critical Care Medicine|
|出版狀態||已發佈 - 十一月 15 2012|
- Cancer immunity
- Myeloid-derived suppressor cell
- Non-small cell lung cancer
ASJC Scopus subject areas