Abstract
BackgroundNatural cytotoxicity, mediated by natural killer (NK) cells plays an important role in the inhibition and elimination of malignant tumor cells. To investigate the immunoregulatory role of NK cells and their potential as diagnostic markers, NK cell activity (NKA) was analyzed in prostate cancer (PCa) patients with particular focus on NK cell subset distribution.MethodsProspective data of NKA and NK cell subset distribution patterns were measured from 51 patients initially diagnosed with PCa and 54 healthy controls. NKA was represented by IFN-γ levels after stimulation of the peripheral blood with Promoca®. To determine the distribution of NK cell subsets, PBMCs were stained with fluorochrome-conjugated monoclonal antibodies. Then, CD16+CD56dim and CD16−CD56bright cells gated on CD56+CD3− cells were analyzed using a flow-cytometer.ResultsNKA and the proportion of CD56bright cells were significantly lower in PCa patients compared to controls (430.9 pg/ml vs. 975.2 pg/ml and 2.3% vs. 3.8%, respectively; p<0.001). Both tended to gradually decrease according to cancer stage progression (p for trend = 0.001). A significantly higher CD56dim-to-CD56bright cell ratio was observed in PCa patients (41.8 vs. 30.3; p<0.001) along with a gradual increase according to cancer stage progression (p for trend = 0.001), implying a significant reduction of CD56bright cells in relation to the alteration of CD56dim cells. The sensitivity and the specificity of NKA regarding PCa detection were 72% and 74%, respectively (best cut-off value at 530.9 pg/ml, AUC = 0.786).ConclusionsReduction of CD56bright cells may precede NK cell dysfunction, leading to impaired cytotoxicity against PCa cells. These observations may explain one of the mechanisms behind NK cell dysfunction observed in PCa microenvironment and lend support to the development of future cancer immunotherapeutic strategies.
Highlights
Natural killer (NK) cells serve a major role in the innate and adaptive immune responses against tumor transformation or pathogen-infected cells [1]
Our findings indicate that immunoregulation in prostate cancer (PCa) is impaired due to a reduction in NK cell activity (NKA) preceded by redistribution of natural killer (NK) cell subsets
A significantly higher CD56dim-to-CD56bright NK cell ratio was observed in patients compared to controls, with a tendency to increase according to stage progression (p for trend = 0.001) (Table 2)
Summary
Natural killer (NK) cells serve a major role in the innate and adaptive immune responses against tumor transformation or pathogen-infected cells [1]. NK cells exert natural cytotoxicity to eliminate malignant cells without prior sensitization or class I MHC restriction [1,2]. CD56bright cells mediate low cytotoxicity but acquire greater cytolytic activity than CD56dim cells upon activation due to release of proinflammatory cytokines such as IFN-c [7]. The level of IFN-c, i.e., NKA, is generally associated with oncological prognosis, which implies the essential role of differential NK cell subset expression in the immune regulation of tumor cells [8]. Natural cytotoxicity, mediated by natural killer (NK) cells plays an important role in the inhibition and elimination of malignant tumor cells. To investigate the immunoregulatory role of NK cells and their potential as diagnostic markers, NK cell activity (NKA) was analyzed in prostate cancer (PCa) patients with particular focus on NK cell subset distribution
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