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

Our plain-English summary of Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma, by S.C. Kao, Y.Y. Cheng, M. Williams, et al (Journal of Thoracic Oncology, 2017).

The study

• Authors: S.C. Kao, Y.Y. Cheng, M. Williams, M.B. Kirschner, J. Madore, T. Lum, K.H. Sarun, A. Linton, B. McCaughan, S. Klebe, N. van Zandwijk, R.A. Scolyer, M.J. Boyer, W.A. Cooper, G. Reid
• Journal: Journal of Thoracic Oncology
• Published: 2017;12(9):1421-1433
• Cited by: 131 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This laboratory study looked at PD-L1 in malignant pleural mesothelioma. PD-L1 is a protein that can help tumours avoid the immune system. The authors stained tumour samples from 72 patients operated on (pleurectomy, with or without decortication) in Sydney between 1992 and 2007. The article did not report on asbestos exposure. Of the 72 tumours, 18 (25%) were PD-L1 positive, and positive staining was more common in non-epithelioid tumours. Median overall survival was 4.0 months for patients with PD-L1-positive tumours and 9.2 months for those with PD-L1-negative tumours. After adjustment for age, gender and tumour subtype, the hazard ratio for PD-L1 positivity was 2.2 (95% confidence interval 1.2 to 4.1). In 63 patients, levels of several tumour suppressor microRNAs were lower in PD-L1-positive tumours. In cell lines, adding miR-15a or miR-16 lowered PD-L1 in MSTO and VMC23 cells but did not change PD-L1 mRNA in H28 cells. The authors noted that most patients received no chemotherapy and that the group had a higher than average share of non-epithelioid tumours. The authors concluded that these data suggest tumour suppressor microRNAs contribute to PD-L1 regulation in this disease.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining analysis of stored tumour samples from a surgical patient series (with survival analysis) and experiments in mesothelioma cell lines
• Who was studied: 72 patients with malignant pleural mesothelioma who had pleurectomy with or without decortication at Royal Prince Alfred Hospital, Sydney, 1992 to 2007, out of 74 consecutive patients. The microRNA analysis covered 63 of them (13 PD-L1 positive, 50 PD-L1 negative). The study also used the MPM cell lines MSTO, H28 and VMC23 and the mesothelial line MeT-5A.
• Exposure: No asbestos or fiber exposure was studied. The study measured PD-L1 protein and microRNA levels in tumours, and tested microRNA mimics in cell lines.
• Main results:
  • 18 of 72 patients (25%) had PD-L1-positive tumours, defined as 5% or more membranous staining
  • PD-L1 positivity was more common in non-epithelioid than epithelioid tumours (p=0.01). Of the 18 positive cases, 14 were non-epithelioid, compared with 23 of the 54 negative cases.
  • Median overall survival was 4.0 months in PD-L1-positive patients and 9.2 months in PD-L1-negative patients (p<0.001)
  • After adjustment for gender, age and histological subtype, PD-L1 positivity remained an adverse prognostic indicator: hazard ratio 2.2 (95% CI 1.2 to 4.1; p<0.01)
  • Median miR-16 level was lower in PD-L1-positive tumours (13 patients) than in PD-L1-negative tumours (50 patients): 0.72 vs. 1.12, p=0.009
  • Median miR-15b level was lower in PD-L1-positive than PD-L1-negative tumours: 0.67 vs. 1.03, p=0.002. miR-195 was also lower (0.63 vs. 1.07, p=0.002). The difference for miR-15a was not statistically significant (0.72 vs. 1.10, p=0.131).
  • Median miR-200c level was lower in PD-L1-positive than PD-L1-negative tumours: 0.37 vs. 0.83, p=0.009. For miR-200b the figures were 0.47 vs. 0.98, p=0.050, which the authors described as a trend that did not reach statistical significance.
  • Median miR-193a-3p level was lower in PD-L1-positive tumours (0.58 vs. 1.17, p=0.039)
  • Other microRNAs tested, including the three miR-34 family members, did not differ between PD-L1-positive and PD-L1-negative tumours
  • In cell lines, miR-15a, miR-15b or miR-16 mimics reduced PD-L1 mRNA in MSTO cells and, to a lesser extent, in VMC23 cells, but not in H28 cells
  • miR-15a or miR-16 mimics reduced PD-L1 protein to background levels in MSTO and VMC23 cells. PD-L1 staining in H28 cells was very low.
  • A miR-193a-3p mimic reduced PD-L1 protein in VMC23 cells only
  • In cell lines, the authors' data suggested that IRF1 contributes to the IFN-gamma-induced, but not the basal, production of PD-L1
• The authors' conclusion: The authors concluded that PD-L1 expression in MPM is associated with changes in several tumour suppressor microRNAs, which can lower PD-L1 levels in the laboratory. They suggested that, at least in some cases, regulation of PD-L1 could contribute to the tumour suppressor effects of these microRNAs.
• Limitations the authors state:
  • Median survival in this series (7.7 months) was lower than in some other reports, probably because patients were treated between 1992 and 2007, when most received no chemotherapy
  • The cohort had a higher than average proportion of non-epithelioid tumours
  • In the three cell lines there was no significant inverse correlation between microRNA levels and PD-L1, which the authors attributed most likely to low PD-L1 in H28 cells

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: PD-L1, Pleural Mesothelioma, Histological Subtype, Prognosis, Immunohistochemistry, Median Overall Survival, Hazard Ratio, confidence interval.

Related studies

• Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma — T.G. Johnson, K. Schelch, et al. (2018)
• miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma — M. Williams, M.B. Kirschner, et al. (2015)
• MicroRNA expression in lung tissues of asbestos-exposed mice: Upregulation of miR-21 and downregulation of tumor suppressor genes Pdcd4 and Reck — Y. Hiraku, J. Watanabe, et al. (2021)
• ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma — Y.Y. Cheng, M.B. Kirschner, et al. (2013)
• Tumour suppressor microRNAs contribute to drug resistance in malignant pleural mesothelioma by targeting anti-apoptotic pathways — M. Williams, Y.Y. Cheng, et al. (2019)
• MiR-score: a novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma — M.B. Kirschner, Y.Y. Cheng, et al. (2015)

Browse more research in Journal of Thoracic Oncology, or return to medical research.