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 cytokine-treated 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.

目的： II 期黑色素瘤患者发生区域和远处转移的风险很高，可能会受益于新的治疗策略。为了阐明 NK 细胞在 II 期黑色素瘤中的作用，我们对高风险皮肤黑色素瘤患者（IIB 和 IIC 期）与低风险患者（IIC 期）中 NK 细胞的细胞毒活性以及各种激活和抑制受体的表达进行了表征。 IA）。材料和方法：使用天然和细胞因子处理的外周血单核细胞进行功能和表型分析。结果：与 IA-B 期患者相比，IIB-C 期患者的 NK 细胞活性显着降低，激活的 NKG2D 和 CD161 受体的表达也降低，这很可能是由于免疫抑制细胞因子 TGF-β1 的血清水平升高所致。这些病人。有趣的是，用 IFN-α、IL-2、IL-12 或 IL-12 和 IL-18 组合治疗外周血单核细胞，可显着诱导两组黑色素瘤患者的 NK 细胞活性。然而，只有低风险患者在体外接受IFN-α治疗后，NKG2D受体的表达显着增加，并且在接受IFN-α或IL-12治疗后，CD161的表达也显着增加。尽管IL-2在两组患者中均诱导NKG2D表达，但这种增加在高危黑色素瘤中显着较低。结论： NK 细胞参数可作为局部黑色素瘤患者疾病进展的生物标志物。 我们的结果进一步表明，使用 NK 细胞激活细胞因子与 TGF-β1 等免疫抑制因子抑制剂联合使用可能是治疗高危皮肤黑色素瘤患者的一种治疗选择。