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

Tobias A.W. Holderried, Luka De Vos, Emma Grace Bawden, Timo J. Vogt, Joern Dietrich, Romina Zarbl, Friedrich Bootz, Glen Kristiansen, Peter Brossart, Jennifer Landsberg, Dimo Dietrich

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number161
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - Nov 20 2019
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

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    Holderried, T. A. W., De Vos, L., Bawden, E. G., Vogt, T. J., Dietrich, J., Zarbl, R., Bootz, F., Kristiansen, G., Brossart, P., Landsberg, J., & Dietrich, D. (2019). Molecular and immune correlates of TIM-3 (HAVCR2) and galectin 9 (LGALS9) mRNA expression and DNA methylation in melanoma. Clinical Epigenetics, 11(1), [161]. https://doi.org/10.1186/s13148-019-0752-8