Correlation of NKG2D and CD158b receptor expression and NK cell cytotoxicity in metastatic melanoma patients

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The first line of antitumor immune defense is mediated by natural killer (NK) cells, as the main effector subpopulation of the innate immune system. The activity of NK cells is regulated by activating and inhibitory receptors whose balance determines whether tumor target cells will be susceptible to NK cell lysis. In this study we evaluated in 66 metastatic melanoma (MM) patients and 50 controls NK cytotoxic activity by the 51-Cr release assay and the expression of activating NKG2D and CD161 receptors and KIR CD158a and CD158b receptors on CD3-CD16+ NK cells by Flow cytometry. We show that MM patients have significantly impaired NK cell activity compared to healthy controls against K562 and a melanoma, FemX, tumor target cell lines. We show for the first time that the expression of NKG2D and CD161 receptor on CD3-CD16+NK cells of MM patients is significantly lower compared to controls, while the expression of KIR receptors, CD158a and CD158b, on CD3-CD16+ NK did not differ significantly in MM patients compared to controls.Also, the expression of NKG2D, CD161, CD158a and CD158b receptors on CD16^bright and CD16^dim NK cell subsets shows significantly decreased expression of CD161 and CD158b receptors on CD16^bright NK cell subpopulation and the expression of CD158b receptor on CD16^dim NK cell subpopulation in MM patients compared to controls. Further analyses of antigen density indicates a decrease in CD161 and an increase in CD158b fluorescence intensity geomean on CD16^bright NK cell subset. Further analyses indicate a new finding of significant positive correlation of NK cell cytotoxicity of MM patients and expression of NKG2D activating receptor, as well as negative correlation of NK cell cytotoxicity with the expression of CD158b on CD3-CD16+ NK cell subset. Therefore, in this study we show for the first time that impaired NK cell cytotoxicity of MM patients may be due to decreased expression of NKG2D and CD161 receptors on CD3-CD16+ NK cells. In the CD16^bright mature and cytotoxic NK cell subset a significant decrease of CD161 and CD158b receptors, and their unfavorably changed antigen fluorescence intensity geomeans, may contribute to their dysfunction. Moreover, we show that, contrary to healthy controls, a positive correlation between NKG2D activating receptor expression and NK cell cytotoxicity, as well as a negative correlation of NK cell activity and the expression of CD158b receptor in MM patients.