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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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