Journal of Thoracic Oncology 2016 July [Epub ahead of print] [Link]
Kao SC, Cheng YY, Williams M, Kirschner MB, Madore J, Lum T, Sarun KH, Linton A, McCaughan B, Klebe S, van Zandwijk N, Scolyer RA, Boyer MJ, Cooper WA, Reid G
The upregulation of PD-L1 is found in many cancers and contributes to the evasion of the host’s immune defence. In malignant pleural mesothelioma (MPM), PD-L1 expression is associated with non-epithelioid histological subtype and poor prognosis, but the pathways involved in the 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.
PD-L1 expression was analysed by IHC in TMAs prepared from samples from patients undergoing surgery (pleurectomy/decortication). MicroRNA expression was analysed by RT-qPCR. Regulation of PD-L1 expression in cell lines was assessed following transfection with microRNA mimics and siRNAs. Interaction between microRNAs and PD-L1 was analysed using AGO2 immunoprecipitation and a luciferase reporter assay.
In a series of 72 MPM patients, 18 (25 %) had positive PD-L1 staining, and this was more common in patients with non-epithelioid subtype (p=0.01). PD-L1 expression was associated with poor survival (median OS: 4.0 vs. 9.2 months, positive vs. negative PD-L1; p<0.001), and in multivariate analyses, PD-L1 expression remained a significant adverse prognostic indicator (HR 2.2, 95% CI: 1.2-4.1; p<0.01). In the same patient series, PD-L1 expression was also associated with down-regulation of microRNAs previously shown to have tumour 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 predicted to target PD-L1, led to downregulation of PD-L1 mRNA and protein. In addition, miR-193a-3p, with an alternative GU-containing target site, also caused PD-L1 downregulation. CONCLUSIONS: Together, these data suggest that tumour suppressor microRNAs contribute to the regulation of PD-L1 expression in MPM.