Open Access

ORIGINAL ARTICLE

Effect of cytokines on NK cell activity and activating receptor expression in high-risk cutaneous melanoma patients

Katarina Mirjačić Martinović¹, Milica Milićević¹, Annette K Larsen², Radan Džodić^3,4, Vladimir Jurišić⁵, Gordana Konjević^1,4, Ana Vuletić¹

1 Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
2 Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938 and Sorbonne University, Kourilsky building 1st floor, Hôpital Saint-Antoine, 184 rue du Faubourg Saint Antoine, 75571 PARIS Cédex 12 France
3 Surgical Oncology Clinic, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
4 School of Medicine, University of Belgrade, Dr Subotića 8, 11000 Beograd, Serbia
5 Faculty of Medical Sciences, University of Kragujevac, P.BOX 124, 34000 Kragujevac, Serbia

* Corresponding Author: K. Martinović,

European Cytokine Network 2019, 30(4), 160-167. https://doi.org/10.1684/ecn.2019.0440

Accepted 01 November 2019;

Abstract

Objective: Stage II melanoma patients have high risk for regional and distant metastases and may benefit from novel therapeutic strategies. To clarify the role of NK cells in Stage II melanoma, we characterized the cytotoxic activity of NK cells and the expression of various activating and inhibitory receptors in high-risk cutaneous melanoma patients (Stages IIB and IIC) compared to low-risk patients (Stage IA). Materials and Methods: Native and cytokinetreated peripheral blood mononuclear cells were used for functional and phenotypical analyses. Results: Compared to Stage IA-B patients, Stage IIB-C patients showed significantly decreased NK cell activity, as well as decreased expression of the activating NKG2D and CD161 receptors, most likely due to increased serum levels of the immunosuppressive cytokine TGF-β1 in these patients. Interestingly, treatment of periperal blood mononuclear cells with IFN-α, IL-2, IL-12 or the combination of IL-12 and IL-18 significantly induced NK cell activity for both groups of melanoma patients. However, only low-risk patients had a significant increase in the expression of the NKG2D receptor after in vitro treatment with IFN-α, as well as an significant increase in the expression of CD161 after treatment with IFN-α or IL-12. Although IL-2 induced the expression of NKG2D in both groups of patients, this increase was significantly lower in high-risk melanoma. Conclusion: NK cell parameters may be useful as biomarkers of disease progression in localized melanoma patients. Our results further suggest that the use of NK cell-activating cytokines in combination with inhibitors of immunosuppressive factors like TGF-β1 could be a therapeutic option for the treatment of high-risk cutaneous melanoma patients.

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