Elevated Circulating CD4⁺CD25^-Foxp3⁺ Regulatory T Cells in Patients with Nonsmall Cell Lung Cancer

CD4⁺CD25⁺Foxp3⁺ regulatory T (Treg) cell-mediated immunosuppression has been implicated as a crucial mechanism of tumor immune cell escape in nonsmall cell lung cancer (NSCLC). However, little is known concerning the specific role of CD4⁺CD25^-Foxp3⁺ Treg cells in NSCLC. The aim of this study was to investigate the frequency of circulating CD4⁺CD25^-Foxp3⁺ Treg cells and their role in NSCLC. The frequencies of Treg, T helper (Th)1, Th2, and Th17 cells in peripheral blood were separately measured in 36 NSCLC patients and 20 healthy controls (HCs) using flow cytometry. Serum cytokine concentrations were determined using cytometric bead arrays. The frequencies of circulating CD4⁺CD25⁺ T cells and CD4⁺CD25⁺Foxp3⁺ and CD4⁺CD25^-Foxp3⁺ Treg cells were significantly higher in advanced-stage NSCLC patients compared with patients with limited-stage NSCLC. The frequencies of circulating CD4⁺CD25⁺Foxp3⁺ and CD4⁺CD25^-Foxp3⁺ Treg cells were negatively correlated with interleukin (IL)-17, but positively correlated with serum IL-10 levels. In addition, the Th17/CD4⁺CD25^-Foxp3⁺ Treg cell ratios were negatively correlated with serum cytokeratin 19 fragment (CYFRA 21-1) concentrations in patients with NSCLC. Moreover, coculturing CD4⁺CD25^-Foxp3⁺ Treg cells and CD14⁺ monocytes in vitro resulted in a higher frequency of CD206⁺CD14⁺ M2-like monocytes compared with CD14⁺ monocytes. Elevated circulating CD4⁺CD25^-Foxp3⁺ Treg cells may be involved in the pathogenesis of NSCLC.