Regulatory T Cells Suppress Natural Killer Cell Immunity in Patients With Human Cervical Carcinoma

Abstract

ObjectiveTo determine the functional attributes of CD4+ CD25+ regulatory T (Treg) cells by suppressing natural killer (NK) cell activity in human cervical cancer (CC).MethodsTriple-color flow cytometry was used to study the phenotypic expression of CD4+ CD25+ Treg cells and NK cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs). In vitro coculture assays were performed to illustrate the cytokine immunoregulations between Treg cells and NK cells.ResultsSignificantly lower expression ratio of NK cells and higher expression ratio of Treg cells in TILs than PBLs were found. The NK cells displayed significantly higher expression ratio of inhibitory NK receptors (CD158a, CD158b, and NKG2A) and lower expression ratio of activating NK receptors (NKG2D, NKp46, and NKp30) as well as perforin in TILs than PBLs, suggesting the suppressed cytotoxicity of the NK cells in the CC tumor milieu. The expression ratio of transforming growth factor-β1 (TGF-β1) on Treg cells as well as TGF-βRII on Treg cells and NK cells was significantly higher in TILs than PBLs. Further functional in vitro assays demonstrated that NK cell function was suppressed by Treg cells, mimicking the inhibition of TGF-β on NK cells, and interleukin-2/interleukin-15 stimulation was able to restore the NK cell activity.ConclusionsThese findings indicate that Treg cells in TILs may abrogate NK cell cytotoxicity through TGF-β pathway, and therefore, Treg cell elimination may enhance NK cell activity and be a novel therapeutic strategy for CC.