Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
Sci Rep. 2017 Aug 11;7(1):7958. doi: 10.1038/s41598-017-08483-z.
Major progress has been made clinically in inhibiting the programmed death receptor 1 (PD-1)/PD-L1 interaction to enhance T cell-mediated immune function, yet the effectiveness of anti-PD-L1/PD-1 agents in enhancing natural killer (NK) cell's function remains largely unknown. Susceptibilities of cisplatin-resistant A549CisR and H157CisR cells vs. parental cells to the cytotoxic action of NK cells were examined. We found cisplatin-resistant cells more resistant to NK cell cytotoxicity than parental cells. There were constitutively higher expressions of PD-L1 in A549CisR and H157CisR cells than in parental cells in vitro, as well as in H157CisR cell-derived tumors than H157P cell-derived tumors. In contrast, we observed that the expression of PD-1 in NK cells was induced after co-culture with cisplatin-resistant cells. We also observed increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity when neutralizing antibody of PD-1 or PD-L1 was added. Further, we found that the NK group 2, member D (NKG2D) ligand levels were lower in A549CisR and H157CisR cells than in parental cells. Meanwhile, we discovered that the MEK/Erk signaling pathway played a significant role in this regulation, and the addition of a MEK/Erk pathway inhibitor significantly enhanced the PD-L1 Ab effect in enhancing NK cell cytotoxicity to cisplatin-resistant cells.
在抑制程序性死亡受体 1（PD-1）/PD-L1 相互作用以增强 T 细胞介导的免疫功能方面，临床上已经取得了重大进展，但抗 PD-L1/PD-1 药物在增强自然杀伤（NK）细胞功能方面的效果在很大程度上仍然未知。本研究旨在研究顺铂耐药 A549CisR 和 H157CisR 细胞与亲本细胞相比对 NK 细胞细胞毒性作用的敏感性。结果发现，与亲本细胞相比，顺铂耐药细胞对 NK 细胞的细胞毒性作用更具抗性。体外 A549CisR 和 H157CisR 细胞中 PD-L1 的表达水平明显高于亲本细胞，H157CisR 细胞衍生的肿瘤中 PD-L1 的表达水平也明显高于 H157P 细胞衍生的肿瘤。相比之下，我们观察到 NK 细胞与顺铂耐药细胞共培养后 PD-1 的表达被诱导。当加入 PD-1 或 PD-L1 的中和抗体时，我们还观察到顺铂耐药细胞对 NK 细胞细胞毒性作用的敏感性增加。此外，我们发现 A549CisR 和 H157CisR 细胞中 NK 细胞群 2，成员 D（NKG2D）配体的水平明显低于亲本细胞。同时，我们发现 MEK/Erk 信号通路在此调节中起重要作用，并且添加 MEK/Erk 通路抑制剂可显著增强 PD-L1 Ab 增强 NK 细胞对顺铂耐药细胞细胞毒性作用的效果。
