Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
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.
Eur Cytokine Netw. 2019 Dec 1;30(4):160-167. doi: 10.1684/ecn.2019.0440.
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).
Native and cytokine-treated peripheral blood mononuclear cells were used for functional and phenotypical analyses.
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.
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.
Ⅱ期黑色素瘤患者存在区域性和远处转移的高风险，可能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，我们比较了高危皮肤黑色素瘤患者（ⅡB 期和ⅡC 期）与低危患者（ⅠA 期）NK 细胞的细胞毒性活性和各种激活及抑制性受体的表达。
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。
与ⅠA-B 期患者相比，ⅡB-C 期患者的 NK 细胞活性明显降低，激活型 NKG2D 和 CD161 受体表达也降低，这很可能是由于这些患者血清中免疫抑制性细胞因子 TGF-β1 水平升高所致。有趣的是，IFN-α、IL-2、IL-12 或 IL-12 和 IL-18 的组合治疗可显著诱导两组黑色素瘤患者的 NK 细胞活性。然而，只有低危患者在体外用 IFN-α处理后 NKG2D 受体的表达显著增加，用 IFN-α或 IL-12 处理后 CD161 的表达也显著增加。虽然 IL-2 诱导了两组患者 NKG2D 的表达，但高危黑色素瘤患者的增加幅度明显较低。
NK 细胞参数可用作局限性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，联合使用 NK 细胞激活细胞因子和 TGF-β1 等免疫抑制因子抑制剂可能是治疗高危皮肤黑色素瘤患者的一种治疗选择。
