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Clin Epigenetics. 2019 Nov 20;11(1):161. doi: 10.1186/s13148-019-0752-8.

Molecular and immune correlates of TIM-3 (HAVCR2) and galectin 9 (LGALS9) mRNA expression and DNA methylation in melanoma.

Author information

1
Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
2
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
3
Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
4
Institute of Experimental Oncology (IEO), University Hospital Bonn, Bonn, Germany.
5
Department of Microbiology & Immunology, The University of Melbourne at the Peter Doherty Institute for Infection & Immunity, Melbourne, VIC, Australia.
6
Institute of Pathology, University Hospital Bonn, Bonn, Germany.
7
Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.
8
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany. dimo.dietrich@gmail.com.

Abstract

BACKGROUND:

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.

KEYWORDS:

Biomarker; DNA methylation; Galectin 9; HAVCR2; Immunotherapy; LGALS9; Melanoma; Prediction; Prognosis; TIM-3

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