Pan Xiaohui, Li Run, Guo Hongjie, Zhang Wenxin, Xu Xiaqing, Chen Xi, Ding Ling
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
The Second Clinical College, Zhejiang Chinese Medical University, Hangzhou, China.
Front Pharmacol. 2021 Jan 13;11:539261. doi: 10.3389/fphar.2020.539261. eCollection 2020.
Programmed death ligand 1 (PD-L1) which is upregulated in various epithelial tumors, plays a central role in the evasion of the immune system. In addition to monoclonal antibodies that blocking PD1/PD-L1 axis, finding small molecule compounds that can suppress PD-L1 expression might be another substitutable strategy for PD1/PD-L1 based therapy. Here, we found that dihydropyridine calcium channel blockers dose-dependently reduced the expression of PD-L1, both in the cytoplasm and cell surface. IFNγ induced PD-L1 transcription was consistently suppressed by Lercanidipine in 24 h, whereas, the half-life of PD-L1 protein was not significantly affected. IFNγ trigged significant STAT1 phosphorylation, which was eliminated by Lercanidipine. Similarly, STAT1 phosphorylation could also be abolished by extracellular calcium chelating agent EGTA and intracellular calcium chelator BAPTA-AM. Furthermore, Lercanidipine enhanced killing ability of T cells by down-regulating PD-L1. Taken together, our studies suggest that calcium signal is a crucial factor that mediates the transcription of PD-L1 and regulation of calcium can be used as a potential strategy for PD-L1 inhibition.
程序性死亡配体1（PD-L1）在多种上皮肿瘤中上调，在逃避免疫系统方面发挥核心作用。除了阻断PD1/PD-L1轴的单克隆抗体外，寻找能够抑制PD-L1表达的小分子化合物可能是基于PD1/PD-L1治疗的另一种替代策略。在此，我们发现二氢吡啶类钙通道阻滞剂可剂量依赖性地降低细胞质和细胞表面的PD-L1表达。乐卡地平在24小时内持续抑制IFNγ诱导的PD-L1转录，而PD-L1蛋白的半衰期未受到显著影响。IFNγ引发显著的STAT1磷酸化，而乐卡地平可消除这种磷酸化。同样，细胞外钙螯合剂EGTA和细胞内钙螯合剂BAPTA-AM也可消除STAT1磷酸化。此外，乐卡地平通过下调PD-L1增强T细胞的杀伤能力。综上所述，我们的研究表明钙信号是介导PD-L1转录的关键因素，调节钙可作为抑制PD-L1的潜在策略。
