Open Access

ORIGINAL ARTICLE

Interleukin-4-induced natural killer cell antitumor activity in metastatic melanoma patients

Ana M. Vuletić¹, Gordana M. Konjević^1,2, Annette K. Larsen³, Nada L. Babović⁴, Vladimir B. Jurišić⁵, Ana Krivokuća¹, Katarina M. Mirjačić Martinović¹

1 Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia 2 School of Medicine, University of Belgrade, Dr Subotića 8, 11000 Beograd, Serbia 3 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 4 Department of Medical Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia 5 Faculty of Medical Sciences, University of Kragujevac, P.BOX 124, 34000 Kragujevac, Serbia

* Corresponding Author: VB. Jurisˇic´,

European Cytokine Network 2020, 31(3), 104-112. https://doi.org/10.1684/ ecn.2020.0449

Accepted 12 July 2020;

Abstract

NK cells are important effectors of innate immunity that mount the first line of defense toward tumor growth. Interleukin-4 (IL-4) has recently been shown to regulate NK cell function, although its role in the regulation of NK cell function in cancer patients has not been clarified. The aim of this study was to investigate the effect of IL-4 on the function and the receptor characteristics of CD16-defined NK cells and their cytotoxic CD16bright and regulatory CD16dim subsets. Peripheral blood lymphocytes obtained from 36 metastatic melanoma (MM) patients treated for 18 h with 10 ng/mL IL-4 were evaluated for NK cell cytotoxicity using the radioactive 51chromium release assay. Expression of the activating receptors NKG2D and CD161, as well as the inhibitory receptors CD158a and CD158b, was analyzed on CD3-CD16+ NK cells and their subsets by flow cytometry. IL-4 induced significant in vitro enhancement of NK cell activity, as well as increased expression of the CD107a degranulation marker, by CD3-CD16dim NK cells. NKG2D expression was also increased on CD3-CD16+ cells by IL-4 with no alteration of the expression of CD161 and inhibitory KIR receptors. Although in vitro treatment with IL-4 increased both the expression of NKG2D and the cytotoxicity of NK cells, it had no detectable effect on the transcription of the TGF-β gene in NK cells of MM patients. The IL-4-induced NK cell cytotoxicity and increased activating NKG2D receptor expression may indicate an important antitumor effect of IL-4 with a potential application for immunotherapy of MM patients.

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