In:
Clinical Epigenetics, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2019-12)
Abstract:
The T cell immunoglobulin and mucin-domain containing-3 receptor TIM-3 (also known as hepatitis A virus cellular receptor 2, encoded by HAVCR2 ) and its ligand galectin 9 ( LGALS9 ) are promising targets for immune checkpoint inhibition immunotherapies. However, little is known about epigenetic regulation of the encoding genes. This study aimed to investigate the association of TIM - 3 and LGALS9 DNA methylation with gene expression, patients’ survival, as well as molecular and immune correlates in malignant melanoma. Results Methylation of all six TIM - 3 CpGs correlated significantly with TIM-3 mRNA levels ( P ≤ 0.05). A strong inverse correlation (Spearman’s ρ = − 0.49) was found in promoter regions, while a strong positive correlation ( ρ = 0.63) was present in the gene body of TIM - 3 . High TIM-3 mRNA expression (hazard ratio (HR) = 0.88, 95% confidence interval (CI) [0.81–0.97], P = 0.007) was significantly associated with better overall survival. Seven of the eight LGALS9 CpG sites correlated significantly with LGALS9 mRNA levels ( P ≤ 0.003). Methylation at five CpG sites showed a strong inverse correlation (Spearman’s ρ = − 0.67) and at two sites a weak positive correlation (Spearman’s ρ = 0.15). High LGALS9 mRNA expression was significantly associated with increased overall survival (HR = 0.83, 95%CI [0.75–0.93], P = 0.001). In addition, we found significant correlations between TIM - 3 and LGALS9 methylation and mRNA expression with immune cell infiltrates and significant differences among distinct immune cell subsets. Conclusions Our study points toward an epigenetic regulation of TIM - 3 and LGALS9 via DNA methylation and might provide an avenue for the development of a predictive biomarker for response to immune checkpoint blockade.
Type of Medium:
Online Resource
ISSN:
1868-7075
,
1868-7083
DOI:
10.1186/s13148-019-0752-8
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2019
detail.hit.zdb_id:
2553921-8
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