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

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).