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Decreased expression of NKG2D, NKp46, DNAM-1 receptors, and intracellular perforin and STAT-1 effector molecules in NK cells and their dim and bright subsets in metastatic melanoma patients

Mirjačić Martinović, Katarina M.a; Babović, Nada Lj.b; Džodić, Radan R.c,d; Jurišić, Vladimir B.f; Tanić, Nikola T.e; Konjević, Gordana M.a,d

doi: 10.1097/CMR.0000000000000072

Although natural killer (NK) cells play an important antitumor role, melanoma cells may affect their effector functions. In this study, we analyzed the expression of various receptors and effector molecules in NK cells and their subsets in metastatic melanoma (MM) patients compared with healthy controls (HCs). In HC and MM patients, we analyzed NK cell activity using a chromium release assay and the expression of CD107a degranulation marker, activating NKG2D, NKp46, DNAM-1, and inhibitory CD158a and CD158b receptors, IL-12R beta 1, IL-12R beta 2, intracellular interferon (IFN)-γ, perforin, and STAT-1 in CD3-CD56+ NK cells, and cytotoxic CD3-CD56dim and immunoregulatory CD3-CD56bright subsets by flow cytometry. MM patients compared with HC not only had significantly decreased NK cell activity, lower expression of CD107a, and impaired IFN-γ production but also had decreased expression of activating NKG2D, NKp46, and DNAM-1 receptors, which was followed by lower expression of perforin, STAT-1, and both IL-12R subunits in NK cells. In MM patients only, there was a positive correlation between NKG2D expression and degranulation capacity, as well as IFN-γ production in NK cells. Analysis of the expression of various parameters of NK cell effector functions between MM patients with different localization of distant metastases showed that patients in the unfavorable M1c subclass had decreased expression of NKG2D and NKp46 on NK cells compared with patients in the M1a+b group. Downregulated NKG2D, NKp46, and DNAM-1 receptors associated with impaired NK cell effector function are important biomarkers of advanced disease with a poor prognosis in melanoma patients.

Departments of aExperimental Oncology

bMedical Oncology

cSurgical Oncology Clinic, Institute of Oncology and Radiology of Serbia

dSchool of Medicine, University of Belgrade

eDepartment of Neurobiology, Institute for Biological Research ‘Siniša Stanković’, University of Belgrade, Belgrade

fFaculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

Correspondence to Katarina M. Mirjačić Martinović, MD, MSc, 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:

Received November 5, 2013

Accepted March 11, 2014

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins