Background/Objectives:Melanoma is a highly malignant skin tumor with poor response to conventional chemotherapeutic regimens. Melanoma cells induce cytotoxic T cell-mediated immune responses, and immunotherapy has significantly improved survival rates for patients with advanced disease.Methods: Here, we investigate NK cell-mediated melanoma cell killing and its regulation by PD-L1/PD-1 blockade and IFNβ. Four melanoma cell lines were used in this study. To evaluate NK cell cytotoxicity, cells were exposed to NK cells with or without IFNβ. The calcein release assay was used to measure cell death, while specific inhibitors and siRNA silencing were applied to determine the contribution of individual effector pathways.Results: NK cells were able to kill melanoma cells with sensitivity to killing varying between different cell lines. Cytotoxic effects were mainly mediated through activation of the TRAIL signaling cascade. In cell lines with low sensitivity to NK cell killing, expression of PD-L1 was noted and killing by NK cells could be significantly increased by inhibition of the PD-L1/PD-1 checkpoint. Killing of melanoma cells could be further increased by incubation of NK cells with IFNβ.Conclusions: Our results point to a role of NK cells in the killing of melanoma cells and a potential clinical benefit of a combination therapy of IFNβ and anti-PD-1 antibody.
背景/目的：黑色素瘤是一种高度恶性的皮肤肿瘤，对常规化疗方案反应不佳。黑色素瘤细胞可诱导细胞毒性T细胞介导的免疫反应，而免疫疗法已显著提高晚期患者的生存率。方法：本研究探讨NK细胞介导的黑色素瘤细胞杀伤作用及其受PD-L1/PD-1阻断和IFNβ的调控机制。实验采用四种黑色素瘤细胞系，通过钙黄绿素释放法检测细胞死亡，并运用特异性抑制剂及siRNA沉默技术评估不同效应通路的贡献。结果：NK细胞能够杀伤黑色素瘤细胞，但不同细胞系对杀伤的敏感性存在差异。细胞毒性作用主要通过激活TRAIL信号通路介导。在对NK细胞杀伤敏感性较低的细胞系中，观察到PD-L1的表达，且抑制PD-L1/PD-1检查点可显著增强NK细胞的杀伤效果。用IFNβ预处理NK细胞可进一步强化其对黑色素瘤细胞的杀伤作用。结论：本研究证实NK细胞在黑色素瘤细胞杀伤中发挥重要作用，并提示IFNβ联合抗PD-1抗体疗法可能具有临床获益潜力。
肿瘤(癌症)患者之家