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Promoter hypomethylation of NY-ESO-1, association with clinicopathological features and PD-L1 expression in non-small cell lung cancer

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posted on 2023-04-06, 01:51 authored by Anderly C Chüeh, Mun-Sem Liew, Prudence A Russell, Marzena Walkiewicz, Aparna Jayachandran, Maud HW Starmans, Paul C Boutros, Gavin Wright, Stephen A Barnett, John MariadasonJohn Mariadason, Thomas John
Cancer-Testis antigens (CTA) are immunogenic molecules with normal tissue expression restricted to testes but with aberrant expression in up to 30% of nonsmall 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.

Funding

This study was supported in part by Pfizer Australia Cancer Grant WI180223 (MSL), National Health and Medical Research Council Australia Postgraduate Scholarship (MSL); NHMRC Early Career Fellowship (TJ), Victorian Cancer Agency (TJ), Cancer Council Victoria (TJ), Ludwig Institute for Cancer Research (AC), Ontario Institute for Cancer Research (PCB), Terry Fox Research Institute New Investigator Award (PCB), CIHR New Investigator Award (PCB), and the Victorian Government operational infrastructure support program.

History

Publication Date

2017-05-23

Journal

Oncotarget

Volume

8

Issue

43

Pagination

13p. (p. 74036-74048)

Publisher

Impact Journals

ISSN

1949-2553

Rights Statement

© Chüeh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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