ORIGINAL ARTICLES: Basic researchBeneficial in-vitro effects of interleukin-2, interleukin-12, and their combination on functional and receptor characteristics of natural killer cells in metastatic melanoma patients with normal serum lactate dehydrogenase levelsMirjačić Martinović, Katarina M.a; Babović, Nada Lj.b; Džodić, Radan R.d,e; Jurišić, Vladimir B.g; Ninković, Aleksandra Z.c; Konjević, Gordana M.a,fAuthor Information Departments of aExperimental Oncology bMedical Oncology cBiochemistry dSurgical Oncology Clinic, Institute of Oncology and Radiology of Serbia Departments of eSurgery fOncology, School of Medicine, University of Belgrade, Belgrade gDepartment of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia Correspondence to Katarina M. Mirjačić Martinović, MD, PhD, Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia Tel: +381 11 2067 290; fax: +381 11 2685 300; e-mail: [email protected] Melanoma Research: December 2016 - Volume 26 - Issue 6 - p 551-564 doi: 10.1097/CMR.0000000000000289 Buy Metrics Abstract Considering tumor-mediated suppression of natural killer (NK) cells, the aim of this study was to investigate the in-vitro effects of interleukin (IL)-2 and IL-12, as immunostimulatory cytokines, on the functional and receptor characteristics of NK cells and their subsets in healthy control (HC) and metastatic melanoma (MM) patients. Peripheral blood mononuclear cells of 27 HC and 35 MM patients were stimulated in vitro with IL-2, IL-12, and their combination for functional and phenotypic analysis. IL-2, IL-12, and primarily their combination, significantly induced NK cell activity, CD107a degranulation marker, and perforin expression in NK cells and their subsets in HC and MM patients. Furthermore, the combination of IL-2 and IL-12 was significantly more efficient than IL-12 alone in the augmentation of NK cell cytotoxicity and CD107a expression. Also, IL-2 and IL-12 reciprocally upregulated each other’s receptors, IL-2Rα and IL-12Rβ1/β2, on NK cells and their subsets in MM and HCs. In addition, the priming of NK cells with IL-2 before IL-12 treatment led to an increase in the expression of both IL-12 receptors. In contrast to IL-12, IL-2 increased activating NKG2D and DNAM-1, as well as inhibitory CD158a and CD158b KIRs. In addition, the cytokines investigated exerted a more potent effect on the increase in NK cell activity and the expression of various NK cell receptors in MM patients with normal lactate dehydrogenase (LDH) serum levels. Therefore, serum LDH could represent a predictor of response to cytokine immunotherapy in MM patients. The optimization of combined IL-2/IL-12 therapy is needed to enhance NK cell functions in MM patients stratified by their LDH levels. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.