Reduction of CD16-CD56bright NK cell subset precedes NK cell dysfunction in prostate cancer

Abstract

Introduction: Natural cytotoxicity, mediated by natural killer (NK) cells is known to play an important role in inhibition and elimination of malignant tumor cells. In order to investigate the immunoregulatory role of NK cells and potential as a diagnostic tool, NK cell activity of prostate cancer (PCa) patients were analyzed with particular focus on NK cell subset distribution.Materials and Methods: The study was based on a prospective cross-sectional analysis of 51 patients initially diagnosed with PCa and 54 healthy controls. NK cell activity and NK cell subset distribution patterns were analyzed. NK cell activity was represented by levels of IFN-γ after stimulation of peripheral blood with proinflammatory cytokines. For distribution of NK cell subsets, PBMCs were stained with FITC-anti-CD3, Alexa Fluor® 647-anti-CD16, and PE-anti-CD56 monoclonal antibodies. Then, CD16+CD56dim and CD16-CD56bright cells gated on CD56+CD3- cells were analyzed by LSRII flow cytometer.Results: Significant associations between NK cell-related factors and clinicopathological data were evident. NK cell activity was significantly lower in patients compared to controls (430.9 pg/ml vs. 975.2 pg/ml; p < 0.001). Moreover, patients with higher stages tended to show greater reduction in NK cell activity (stages II-IV: 546.1 pg/ml, 427.8 pg/ml, and 194.5 pg/ml; p for trend = 0.001). The proportion of CD56bright cells was lower in patients (2.48 % vs. 4.13 %; p<0.001). According to stage progression, CD56bright cells tended to gradually reduce (2.74 %, 2.21 %, and 1.72 %; p for trend < 0.001) in relation to CD56dim cells, confirmed by an increase in CD56dim to CD56bright cell ratio (p for trend = 0.001). The sensitivity and specificity of NK cell activity regarding PCa detection were 72% and 74%, respectively (best cut-off value at 530.9 pg/ml, AUC = 0.786 ± 0.051).Conclusions: Results of the

present study implicate that reduction of CD56bright cells may precede NK cell dysfunction, leading to impaired cytolytic activity against PCa cells. These observations may explain one of the mechanisms behind immunoregulatory function of NK cells, and lend further support to potential immunotherapeutic strategies for tumor.