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J Thorac Oncol. 2017 Sep;12(9):1421-1433. doi: 10.1016/j.jtho.2017.05.024. Epub 2017 Jun 16.

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

Author information

1
Asbestos Diseases Research Institute, Sydney, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia.
2
Asbestos Diseases Research Institute, Sydney, Australia.
3
Asbestos Diseases Research Institute, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia.
4
Sydney Medical School, The University of Sydney, Sydney, Australia; Melanoma Institute Australia, Sydney, Australia.
5
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.
6
Asbestos Diseases Research Institute, Sydney, Australia; Department of Medical Oncology, Concord Cancer Centre, Sydney, Australia.
7
Sydney Medical School, The University of Sydney, Sydney, Australia; Sydney Cardiothoracic Surgeons, RPAH Medical Centre, Sydney, Australia.
8
Department of Anatomical Pathology, Flinders University and SA Pathology at Flinders Medical Centre, Adelaide Australia.
9
Sydney Medical School, The University of Sydney, Sydney, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia; Department of Medical Oncology, Concord Cancer Centre, Sydney, Australia.
10
Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia.
11
Sydney Medical School, The University of Sydney, Sydney, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia; School of Medicine, Western Sydney University, Sydney, Australia.
12
Asbestos Diseases Research Institute, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia. Electronic address: glen.reid@sydney.edu.au.

Erratum in

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.

KEYWORDS:

Malignant pleural mesothelioma; MicroRNA; PD-L1; Prognosis

PMID:
28629895
DOI:
10.1016/j.jtho.2017.05.024
[Indexed for MEDLINE]
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