Promoter hypomethylation of NY-ESO-1, association with clinicopathological features and PD-L1 expression in non-small cell lung cancer
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Anderly C. Chüeh1,2,*, Mun-Sem Liew1,2,3,*, Prudence A. Russell4, Marzena Walkiewicz1,3, Aparna Jayachandran1,3,5, Maud H.W. Starmans6, Paul C. Boutros6,7,8, Gavin Wright9, Stephen A Barnett10, John M. Mariadason1,2,3,5 and Thomas John1,2,3
1Ludwig Institute of Cancer Research, Melbourne-Austin Branch, Victoria, Australia
2Department of Medicine, Austin Health, University of Melbourne, Victoria, Australia
3Olivia Newton-John Cancer Research Institute, Victoria, Australia
4Department of Anatomical Pathology, St Vincent’s Hospital, Victoria, Australia
5School of Cancer Medicine, La Trobe University, Victoria, Australia
6Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada
7Department of Medical Biophysics, University of Toronto, Toronto, Canada
8Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada
9Department of Thoracic Oncology, St Vincent’s Hospital, Victoria, Australia
10Department of Thoracic Surgery, Austin Hospital, Melbourne, Victoria, Australia
*These authors contributed equally to this work
Thomas John, email: [email protected]
Keywords: NY-ESO-1, promoter methylation, PD-L1, biomarker, lung cancer
Received: February 28, 2017 Accepted: May 01, 2017 Published: May 23, 2017
Cancer-Testis antigens (CTA) are immunogenic molecules with normal tissue expression restricted to testes but with aberrant expression in up to 30% of non-small cell lung cancers (NSCLCs). Regulation of CTA expression is mediated in part through promoter DNA methylation. Recently, immunotherapy has altered treatment paradigms in NSCLC. Given its immunogenicity and ability to be re-expressed through demethylation, NY-ESO-1 promoter methylation, protein expression and its association with programmed death receptor ligand-1 (PD-L1) expression and clinicopathological features were investigated. Lung cancer cell line demethylation resulting from 5-Aza-2′-deoxycytidine treatment was associated with both NY-ESO-1 and PD-L1 re-expression in vitro but not increased chemosensitivity. NY-ESO-1 hypomethylation was observed in 15/94 (16%) of patient samples and associated with positive protein expression (P < 0.0001). In contrast, PD-L1 expression was observed in 50/91 (55%) but strong expression in only 12/91 (13%) cases. There was no association between NY-ESO-1 and PD-L1 expression, despite resultant re-expression of both by 5-Aza-2′-deoxycytidine. Importantly, NY-ESO-1 hypomethylation was found to be an independent marker of poor prognosis in patients not treated with chemotherapy (HR 3.59, P = 0.003) in multivariate analysis. In patients treated with chemotherapy there were no differences in survival associated with NY-ESO-1 hypomethylation. Collectively, these results provided supporting evidence for the potential use of NY-ESO-1 hypomethylation as a prognostic biomarker in stage 3 NSCLCs. In addition, these data highlight the potential to incorporate demethylating agents to enhance immune activation, in tumours currently devoid of immune infiltrates and expression of immune checkpoint genes.
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