Research Papers:
PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p
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Abstract
Valentina Audrito1,2,*, Sara Serra1,2,*, Aureliano Stingi1,2, Francesca Orso3, Federica Gaudino1,2, Cinzia Bologna1,2, Francesco Neri1, Giulia Garaffo3, Romina Nassini4, Gianna Baroni5, Eliana Rulli6, Daniela Massi5, Salvatore Oliviero1,7, Roberto Piva3, Daniela Taverna3, Mario Mandalà8,**, Silvia Deaglio1,2,**
1Human Genetics Foundation (HuGeF), Turin, Italy
2Department of Medical Sciences, University of Turin, Turin, Italy
3Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
4Department of Health Sciences, University of Florence, Italy
5Department of Surgery and Translational Medicine, University of Florence, Italy
6Methodology for Clinical Research Laboratory, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
7Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy
8Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy
*These authors have contributed equally to this work
**These authors have shared last authorship
Correspondence to:
Silvia Deaglio, email: [email protected], [email protected]
Keywords: melanoma, targeted therapy, resistance to therapy, microRNA, regulation of gene expression
Received: August 11, 2016 Accepted: January 06, 2017 Published: February 09, 2017
ABSTRACT
PD-L1 is expressed by a subset of patients with metastatic melanoma (MM) with an unfavorable outcome. Its expression is increased in cells resistant to BRAF or MEK inhibitors (BRAFi or MEKi). However, the function and regulation of expression of PD-L1 remain incompletely understood.
After generating BRAFi- and MEKi-resistant cell lines, we observed marked up-regulation of PD-L1 expression. These cells were characterized by a common gene expression profile with up-regulation of genes involved in cell movement. Consistently, in vitro they showed significantly increased invasive properties. This phenotype was controlled in part by PD-L1, as determined after silencing the molecule. Up-regulation of PD-L1 was due to post-transcriptional events controlled by miR-17-5p, which showed an inverse correlation with PD-L1 mRNA. Direct binding between miR-17-5p and the 3’-UTR of PD-L1 mRNA was demonstrated using luciferase reporter assays.
In a cohort of 80 BRAF-mutated MM patients treated with BRAFi or MEKi, constitutive expression of PD-L1 in the absence of immune infiltrate, defined the patient subset with the worst prognosis. Furthermore, PD-L1 expression increased in tissue biopsies after the metastatic lesions became resistant to BRAFi or MEKi. Lastly, plasmatic miR-17-5p levels were higher in patients with PD-L1+ than PD-L1- lesions.
In conclusion, our findings indicate that PD-L1 expression induces a more aggressive behavior in melanoma cells. We also show that PD-L1 up-regulation in BRAFi or MEKi-resistant cells is partly due to post-transcriptional mechanisms that involve miR-17-5p, suggesting that miR-17-5p may be used as a marker of PD-L1 expression by metastatic lesions and ultimately a predictor of responses to BRAFi or MEKi.
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