The influence of NK cell activating and inhibitory receptor expression on the function of these cells in metastatic melanoma patients

Uvod: Melanom, maligni tumor melanocita, iako ima brojna imunogenična svojstva, predstavlja tumor kože sa najvišom incidencom smrtnosti. Za anititumorsku imunost u melanomu posebno su značajne urođenoubilačke (engl. natural killer, NK) ćelije, komponenta sistema urođene imunosti koje mogu neposredno da prepoznaju maligno transformisane ćelije i da ih liziraju citolitičkim enzimima (perforin, granzimi), kao i da produkcijom citokina, pre svega IFN-γ, i hemokina regulišu funkcije ostalih ćelija imunskog odgovora u borbi protiv tumora. NK ćelije se definišu kao CD3-CD56+ i obuhvataju dve funkcionalno i fenotipski različite subpopulacije, zrelu, citotoksičnu CD3-CD56potmulo+ i manje zrelu, imunoregulatornu CD3-CD56sjajno+. Funkcija NK ćelija je regulisna balansom signala koji potiču od njihovih aktivacionih i inhibitornih receptora. Aktivacioni receptori, među kojima lektinu sličan receptor NKG2D (engl. natural killer group 2, member D) ima veoma značajnu ulogu, prepoznaju stresom indukovane ligande na ćelijama tumora, dok inhibitorni imunoglobulinima slični ubilački receptori (engl. immunoglobulin-like killer receptors, KIR) vezivanjem za MHC molekule I klase inhibiraju funkciju NK ćelija i obezbeđuju njihovu toleranciju na sopstvene ćelije. Citokini urođene imunosti, IL-12 i IL-18, koje produkuju, pre svega, dendritične ćelije i makrofagi, kao i IL-2 kao glavni citokin Th1 imunskog odgovora različitim mehanizmima dovode do povećanja proliferacije i aktivacije NK ćelija u borbi protiv tumora. Ciljevi rada: S obzirom da NK ćelije periferne krvi imaju značajnu ulogu u borbi protiv melanoma, a usled imunosupresije u odmaklom stadijumu tumora njihova aktivnost je u velikoj meri izmenjena, od velikog značaja bilo je istraživanje funkcionalnih i imunofenotipskih karakteristika NK ćelija periferne krvi i njihovih subpopulacija u bolesnika obolelih od metastatskog melanoma (MM) u odnosu na zdrave kontrolne (ZK) osobe...Introduction: Melanoma, malignant neoplasm of melanocytes, despite of its immunogenicity is the skin cancer with the highest mortality rate. In antitumor immunity in melanoma, natural killer (NK) cells as the component of the innate immune system have the ability to directly recognize malignantly transformed cells, lyse them by cytolitic enzymes (perforin and granzymes) and by production of cytokines, such as IFN-γ and chemokines regulate the function of the other components of anti-tumor immune response. NK cells are defined as CD3-CD56+ and they are divided in two functionally and phenotipically different subsets, mature, cytotoxic, CD3-CD56dim+ and less mature, immunoregulatory, CD3-CD56bright+. NK cell function is regulated by the balance of signals mediated by their activating and inhibitory receptors. Activating receptors, such as lectin-like receptor, natural killer group 2, member D (NKG2D) recognize stress induced ligands on tumor cells, while the inhibitory immunoglobulin-like killer receptors (KIR) by binding to MHC class I molecules inhibit NK cell function and enable self tolerance of NK cells. IL-12 and IL-18, the innate immunity cytokines produced primarily by dendritic cells and macrophages and IL-2, as the main cytokine of Th1 immune response have the ability to induce NK cell proliferation and activation against melanoma. Objectives: Although the peripheral blood NK cells have an important antimelanoma effect considering the immunosupression in advanced melanoma the effector functions of NK cells are impaired. According to this it was of great importance to analyze the functional and immunophenotypical characteristics of peripheral blood CD3-CD56+ NK cells and their subsets in metastatic melanoma (MM) patients compared to healthy controls (HC). Since melanoma is an immunogenic tumor insensitive to irradiation and chemotherapy and numerous cytokines have stimulatory effect on NK cells, such as IL-2 that was approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma patients and IL-12 and IL-18 that are intensively investigated in numerous preclinical and clinical studies, the aim of this study was to investigate the effects of these cytokines on various functional and phenotypical characteristics of peripheral blood NK cells in MM patients and HC with intention to analyze the mechanisms of activity of these cytokines and their ability to induce anti-tumor NK cell immune response..