Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma

Steven Kao, Yuen Yee Cheng, Marissa Williams, Michaela Kirschner, Jason Madore, Trina Lum, Kadir Sarun, Anthony Linton, Brian McCaughan, Sonja Klebe, Nico van Zandwijk, R. A. Scolyer, Michael Boyer, Wendy Cooper, Glen Reid

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    Abstract

    Introduction The upregulation of programmed death ligand 1 (PD-L1) is found in many cancers and contributes to evasion of the host's immune defense. In malignant pleural mesothelioma (MPM), PD-L1 expression is associated with the nonepithelioid histological subtype and poor prognosis, but the pathways involved in control of PD-L1 expression in MPM are poorly understood. To address one possible means of PD-L1 regulation we investigated the relationship between dysregulated microRNA levels and PD-L1 expression. Methods PD-L1 expression was analyzed by immunohistochemistry in tissue microarrays prepared from samples from patients undergoing an operation (pleurectomy with or without decortication). MicroRNA expression was analyzed by reverse-transcriptase quantitative polymerase chain reaction. Regulation of PD-L1 expression in cell lines was assessed after transfection with microRNA mimics and small interfering RNAs. Interaction between microRNAs and PD-L1 was analyzed by using argonaute-2 immunoprecipitation and a luciferase reporter assay. Results In a series of 72 patients with MPM, 18 (25%) had positive PD-L1 staining, and this was more common in patients with the nonepithelioid subtype (p = 0.01). PD-L1 expression was associated with poor survival (median overall survival 4.0 versus 9.2 months with positive versus negative PD-L1 expression [p < 0.001]), and in multivariate analyses, PD-L1 expression remained a significant adverse prognostic indicator (hazard ratio = 2.2, 95% confidence interval: 1.2–4.1, p < 0.01). In the same patient series, PD-L1 expression was also associated with downregulation of microRNAs previously shown to have tumor suppressor activity in MPM. The median microRNA expression levels of miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c were significantly lower in the PD-L1–positive samples. Transfecting MPM cell lines with mimics corresponding to miR-15a and miR-16, both of which are predicted to target PD-L1, led to downregulation of PD-L1 mRNA and protein. In addition, miR-193a-3p, with an alternative G-U–containing target site, also caused PD-L1 downregulation. Conclusions Together, these data suggest that tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in MPM.

    Original languageEnglish
    Pages (from-to)1421-1433
    Number of pages13
    JournalJournal of Thoracic Oncology
    Volume12
    Issue number9
    DOIs
    Publication statusPublished - Sep 2017

    Keywords

    • Malignant pleural mesothelioma
    • MicroRNA
    • PD-L1
    • Prognosis

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  • Cite this

    Kao, S., Cheng, Y. Y., Williams, M., Kirschner, M., Madore, J., Lum, T., Sarun, K., Linton, A., McCaughan, B., Klebe, S., van Zandwijk, N., Scolyer, R. A., Boyer, M., Cooper, W., & Reid, G. (2017). Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma. Journal of Thoracic Oncology, 12(9), 1421-1433. https://doi.org/10.1016/j.jtho.2017.05.024