CD14⁺S100A9⁺ Myeloid-derived Suppressor Cells Portend Decreased Survival in Patients with Advanced Lung Cancer

It has been clearly shown from multiple preclinical studies that myeloid-derived suppressor cells (MDSC) serve as a target for inhibiting tumor growth (1–3). Although studies in humans have shown the presence of MDSC in different pathological conditions, understanding their clinical significance in cancer requires the full characterization of these cells. The characteristics of MDSC have been described for several human malignancies, including melanoma, colon cancer, and renal cell carcinoma, but the identification of a unique set of markers for human MDSC has been challenging because MDSC gene expression varies in different tumor types.

Feng and colleagues in this issue of the Journal (pp. ) describe the characteristics of the CD11b⁺CD14⁺S100A9⁺ monocytic MDSC and their clinical relevance in patients with advanced non–small cell lung cancer (NSCLC) (4). The identification of markers for the characterization of MDSC in lung cancer is useful because only limited data are available on specific markers. The authors evaluated the characteristics of MDSC in the peripheral blood of patients with NSCLC [adenocarcinoma, 40; squamous cell carcinoma, 6; and nonclassified NSCLC, 6] in comparison to 17 healthy control subjects. In addition, 40 patients who received cisplatin-based chemotherapy in a randomized prospective trial were evaluated for the predictive role of MDSC. The authors demonstrated that there was a higher proportion of CD11b⁺CD14⁺ than CD11b⁺CD14⁻ MDSC in the peripheral blood mononuclear cells of patients with NSCLC, and the frequencies of both subsets were higher in patients with NSCLC in comparison to healthy control subjects. Both subsets of MDSC had similar suppressive activity on CD8 T-cell proliferation and IFN-γ production. In contrast, CD11b⁺CD14⁺ cells from healthy donors showed no suppressive ability on CD8⁺ T-cell proliferation or IFN-γ production. Through inhibitor and antibody-mediated blocking experiments, the authors showed that the CD11b⁺CD14⁺ MDSC–mediated suppression of CD8 T cells in vitro was via arginase, inducible nitric oxide synthase, the IL-13/IL-4Rα axis, and IL-10. The levels of S100A9⁺ expression by CD11b⁺CD14⁺ correlated with their suppressive ability. Furthermore, high levels of CD11b⁺CD14⁺S100A9⁺ MDSC were associated with poor response to cisplatin-based chemotherapy and predicted shorter progression-free survival. Although the CD11b⁺CD14⁻ subpopulation of MDSC had an inhibitory ability that was comparable to the CD11b⁺CD14⁺ cells, there was no association of these cells with performance status or treatment response of patients with NSCLC to chemotherapy. The findings of this study are significant as they show that S100A9 can serve as an important marker for the further characterization of the CD11b⁺CD14⁺ MDSC in patients with advanced NSCLC. The results of this study corroborate the findings from a previous study that demonstrated an increase in the population of CD14⁺ S100A9⁺ MDSC in the peripheral blood from patients with colon cancer in comparison with healthy control subjects (5). Since solid tumors contain a significant population of tumor-infiltrating myeloid cells that promote tumor growth, the lack of evaluation of the characteristics of MDSC from the NSCLC samples is a limitation of this study. It is not known if the CD11b⁺CD14⁺S100A9⁺ MDSC are present in the lung tumor microenvironment of the patients with advanced NSCLC. Nevertheless, the results of this study demonstrate that levels of CD11b⁺CD14⁺S100A9⁺ MDSC in peripheral blood can serve as a predictor of response to chemotherapy in patients with advanced lung cancer. Further investigations are required to determine whether modulating the levels and activities of CD11b⁺CD14⁺S100A9⁺ MDSC would improve patient outcome in advanced lung cancer. MDSC play a central role in immune suppressive pathways and tumor progression, and modulating the activities of this population could prove beneficial as an innovative therapeutic strategy against lung cancer.