Wang Haojie, Qi Yijun, Lan Zijun, Liu Qiwei, Xu Juanjuan, Zhu Mengxi, Yang Tingting, Shi Ruolin, Gao Shegan, Liang Gaofeng
School of Basic Medical Sciences, Henan University of Science & Technology, Luoyang, China.
Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, The First Affiliated Hospital School of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.
Gene Ther. 2023 Feb;30(1-2):88-100. doi: 10.1038/s41434-022-00331-8. Epub 2022 Apr 19.
Chemotherapy resistance remains a major obstacle in the treatment of esophageal cancer. Previous researches have shown that an increase in exosomal PD-L1 expression was positively associated with a more advanced clinical stage, a poorer prognosis as well as drug resistance in patients with esophageal squamous cell carcinoma (ESCC). To explore the role of exosomal PD-L1 in ESCC, we performed bioinformatics analysis as well as several in vitro/in vivo functional experiments in a parental sensitive cell line EC-9706 and its derivative, a paclitaxel-resistant subline EC-9706R, and found that the exosomal PD-L1 from EC-9706R was higher than that from EC-9706. Moreover, exosomes from EC-9706R significantly increased invasion, migration and chemoresistance of EC-9706. Anti-PD-L1 treatment in combination with chemotherapy also led to reduced tumor burden in vivo. Inhibition of the release of exosomes by GW4869 or inhibition of STAT3 phosphorylation by stattic could effectively reverse the resistance to paclitaxel mediated by exosomal PD-L1. Furthermore, we found that PD-L1, miR-21, and multidrug resistance (MDR1) gene are involved in the process of exosomal transfer. Moreover, PD-L1 could enhance miR-21 expression by increasing the enrichment of STAT3 on miR-21 promoter. Our results suggested that exosomal PD-L1 may contribute to drug resistance to paclitaxel by regulating the STAT3/miR-21/PTEN/Akt axis and promote tumorigenic phenotype. This study provides a novel potential therapeutic approach to reverse chemoresistance and tumor progression through exosomal PD-L1 in ESCC patients.
化疗耐药仍然是食管癌治疗中的一个主要障碍。先前的研究表明，外泌体PD-L1表达的增加与食管鳞状细胞癌（ESCC）患者更晚期的临床分期、更差的预后以及耐药性呈正相关。为了探究外泌体PD-L1在ESCC中的作用，我们在亲本敏感细胞系EC-9706及其衍生物、紫杉醇耐药亚系EC-9706R中进行了生物信息学分析以及多项体外/体内功能实验，发现EC-9706R的外泌体PD-L1高于EC-9706的。此外，EC-9706R的外泌体显著增加了EC-9706的侵袭、迁移和化疗耐药性。抗PD-L1治疗联合化疗也导致体内肿瘤负荷降低。GW4869抑制外泌体释放或stattic抑制STAT3磷酸化可有效逆转外泌体PD-L1介导的紫杉醇耐药性。此外，我们发现PD-L1、miR-21和多药耐药（MDR1）基因参与了外泌体转移过程。而且，PD-L1可通过增加STAT3在miR-21启动子上的富集来增强miR-21表达。我们的结果表明，外泌体PD-L1可能通过调节STAT3/miR-21/PTEN/Akt轴导致对紫杉醇的耐药性，并促进肿瘤发生表型。本研究为通过ESCC患者外泌体PD-L1逆转化疗耐药和肿瘤进展提供了一种新的潜在治疗方法。
