Abstract
BackgroundThe 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.ResultsMethylation 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.ConclusionsOur 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.
Highlights
Immunotherapy has revolutionized cancer treatment in recent years
hepatitis A virus cellular receptor 2 gene (HAVCR2) and Galectin 9 (LGALS9) methylation correlates with T cell immunoglobulin and mucin-domain containing-3 (TIM-3) and LGALS9 mRNA expression A total of 14 CpG sites were investigated within the HAVCR2 and LGALS9 gene loci
We found significant inverse correlations between mRNA expression and methylation in the promoter region while a significant and strong positive correlation was present in the gene body and the more intragenic located promoter region
Summary
One main principle of anti-cancer immunotherapy is immune checkpoint blockade (ICB), which was recognized with the Nobel Prize in 2018 [1]. The most aggressive skin cancer, has been at the forefront of ICB [3]. Various other antagonists and agonists targeting additional immune checkpoints are currently under clinical investigation, among them the T cell immunoglobulin and mucin-domain containing-3 (TIM-3) immune checkpoint. The T cell immunoglobulin and mucin-domain containing-3 receptor TIM-3 ( 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. 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
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have