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

Abstract

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.

Serum Antibody Against NY-ESO-1 and XAGE1 Antigens Potentially Predicts Clinical Responses to Anti–Programmed Cell Death-1 Therapy in NSCLC

“…14 Approximately 20% of NSCLC cases reportedly express NY-ESO-1 mRNA, which correlate with protein expression levels. [34][35][36] Among them, lung squamous cell carcinoma is reported to frequently express the NY-ESO-1 antigen with serum Ab in advanced stages, which is consistent with our results for squamous cell carcinoma. 14 NY-ESO-1-specific CD8 þ T cell has been isolated from most patients with NY-ESO-1 Ab, and we also isolated NY-ESO-1-specific CD8 þ T cell after anti-PD-1 therapy (data not shown).…”

Downregulation of DACT-2 by Promoter Methylation and its Clinicopathological Significance in Prostate Cancer

“…As a potent DNA methyltransferase inhibitor, 5-AZA has been used in preclinical and clinical trials to alleviate the patient's symptoms of many diseases including myelodysplastic syndrome, chronic myeloid leukemia, acute myeloid leukemia, acute lymphoid leukemia, melanoma, colorectal cancer, non-small cell lung cancer, and renal cancer16-21and has recently been approved by the Food and Drug Administration for the treatment of myelodysplastic syndrome22. In cell culture studies, 5-AZA has been found to be useful as an inhibitor of transcripts silencing that can restore the expression of DACT-2, which was consistent of many reports concerning DACT-2 hypermethylation in other cancer23-26.…”

Sublethal Radiation Affects Antigen Processing and Presentation Genes to Enhance Immunogenicity of Cancer Cells

“…We previously isolated from human patients cytotoxic CD8 + T cell clones that are NY-ESO-1-specific and restricted to the HLA-A*02 type of class I major histocompatibility complex (MHC) [15]. The NCI-H522 human lung adenocarcinoma cell line (H522) is of the HLA-A*02 type and expresses the CTAG1B gene, although at a low level compared to multiple other NSCLC cell lines [16]. Binding of MHC-I-presented NY-ESO-1 on H522 cell surface to NY-ESO-1-specific T cell receptors activates the T cells, which then secrete interferon γ (IFNγ).…”