Abstract
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.
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The data supporting the findings of this study are available within the article. The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (81972571), Key Science and Technology Program of Henan Province (212102310168) and Innovation Scientists and Technicians Troop Construction Projects of Henan Province (CXTD2017071).
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HJW: Conceptualization, investigation, validation, formal analysis, writing—original draft, writing-review and editing. YJQ: Conceptualization, writing—original draft, formal analysis, supervision. ZJL and JJX: Investigation, validation, and data curation. QWL: Investigation, validation, and funding acquisition. MXZ, TTY, and RLS: Validation, formal analysis. SGG: Conceptualization, investigation supervision. GFL: Conceptualization, writing-review and editing, supervision, project administration, and funding acquisition.
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Wang, H., Qi, Y., Lan, Z. et al. Exosomal PD-L1 confers chemoresistance and promotes tumorigenic properties in esophageal cancer cells via upregulating STAT3/miR-21. Gene Ther 30, 88–100 (2023). https://doi.org/10.1038/s41434-022-00331-8
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DOI: https://doi.org/10.1038/s41434-022-00331-8
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