程序性死亡配体 1/程序性死亡受体 1（PD-L1/PD-1）阻断通过颗粒酶 B 分泌增强自然杀伤细胞对非小细胞肺癌（NSCLC）的细胞毒性。
PD-L1/PD-1 blockage enhanced the cytotoxicity of natural killer cell on the non-small cell lung cancer (NSCLC) by granzyme B secretion.
机构信息
Department of Bioengineering, Pharmacy School of Jilin University, Changchun, 130021, Jilin, China.
Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
出版信息
Clin Transl Oncol. 2023 Aug;25(8):2373-2383. doi: 10.1007/s12094-023-03120-w. Epub 2023 Mar 1.
OBJECTIVE
To explore the role of PD-L1/PD-1 blockage in the cytotoxicity of natural killer cell in NSCLC.
METHODS
Two NSCLC cell lines, Calu-1 and H460, were tested for susceptibility to the cytolytic activity of freshly isolated healthy donor NK cells by a non-radioactive cellular cytotoxicity assay kit. Western blot analysis, FACS, ELISA and antibody blockage experiments were conducted to determine the mechanisms. NK cells isolated from NSCLC patients were also collected for functional assays.
RESULTS
Calu-1 and H460 cells were lysed by NK cells in a dose-dependent manner. H460 cells showed less susceptibility to NK cell-mediated lysis than Calu-1 cells at all ratios. The expression of PD-L1 on H460 cells was higher than that on Calu-1 cells, as determined by FACS and western blot analysis. The specific lysis of H460 cells by NK cells was enhanced when the PD-L1/PD-1 interaction was blocked by anti-PD-L1 antibody. This finding was also demonstrated in NK cells isolated from NSCLC patients.
CONCLUSIONS
The present study revealed that PD-L1/PD-1 blockage enhanced the cytotoxicity of natural killer cells in NSCLC via granzyme B secretion. This study will greatly facilitate the precise treatment of lung cancer through determination of PD-L1 expression in tumors.
目的
探讨 PD-L1/PD-1 阻断在非小细胞肺癌（NSCLC）自然杀伤（NK）细胞细胞毒性中的作用。
方法
采用非放射性细胞毒性检测试剂盒，检测两种 NSCLC 细胞系（Calu-1 和 H460）对新鲜分离的健康供体 NK 细胞细胞溶解活性的敏感性。通过 Western blot 分析、流式细胞术、ELISA 和抗体阻断实验来确定机制。还收集了来自 NSCLC 患者的 NK 细胞进行功能测定。
结果
Calu-1 和 H460 细胞以剂量依赖性方式被 NK 细胞溶解。在所有比例下，H460 细胞对 NK 细胞介导的溶解的敏感性均低于 Calu-1 细胞。通过流式细胞术和 Western blot 分析，发现 H460 细胞 PD-L1 的表达高于 Calu-1 细胞。当用抗 PD-L1 抗体阻断 PD-L1/PD-1 相互作用时，NK 细胞对 H460 细胞的特异性溶解得到增强。这一发现也在来自 NSCLC 患者的 NK 细胞中得到证实。
结论
本研究表明，通过 granzyme B 分泌，PD-L1/PD-1 阻断增强了 NSCLC 中自然杀伤细胞的细胞毒性。这项研究将通过确定肿瘤中 PD-L1 的表达，极大地促进对肺癌的精确治疗。
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