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

CpG Islands DNA Methylation Epigenesis, Genetic Galectins / genetics Gene Expression Regulation, Neoplastic Hepatitis A Virus Cellular Receptor 2 / genetics Humans Melanoma / genetics Prognosis Promoter Regions, Genetic Survival Analysis Up-Regulation
Biomarker DNA methylation Galectin 9 HAVCR2 Immunotherapy LGALS9 Melanoma Prediction Prognosis TIM-3

Journal

Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977

Informations de publication

Date de publication:
20 11 2019
Historique:
received: 20 05 2019
accepted: 23 09 2019
entrez: 22 11 2019
pubmed: 22 11 2019
medline: 28 7 2020
Statut: epublish

Résumé

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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1186/s13148-019-0752-8 PMID: 31747929 PMC: PMC6868848
pubmed: 31747929
doi: 10.1186/s13148-019-0752-8
pii: 10.1186/s13148-019-0752-8
pmc: PMC6868848
doi:

Substances chimiques

Galectins 0
HAVCR2 protein, human 0
Hepatitis A Virus Cellular Receptor 2 0
LGALS9 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

161

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Auteurs

Tobias A W Holderried (TAW)

Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.

Luka de Vos (L)

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.

Emma Grace Bawden (EG)

Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
Institute of Experimental Oncology (IEO), University Hospital Bonn, Bonn, Germany.
Department of Microbiology & Immunology, The University of Melbourne at the Peter Doherty Institute for Infection & Immunity, Melbourne, VIC, Australia.

Timo J Vogt (TJ)

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.

Joern Dietrich (J)

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.

Romina Zarbl (R)

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.

Friedrich Bootz (F)

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.

Glen Kristiansen (G)

Institute of Pathology, University Hospital Bonn, Bonn, Germany.

Peter Brossart (P)

Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.

Jennifer Landsberg (J)

Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.

Dimo Dietrich (D)

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany. dimo.dietrich@gmail.com.
ORCID: 0000-0001-9794-7927

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Classifications MeSH

Recherchemedicale.com › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Ilots CpG › Molecular and immune correlates of TIM-3...
Recherchemedicale.com › Phénomènes génétiques › Méthylation de l'ADN › Molecular and immune correlates of TIM-3...
Recherchemedicale.com › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Molecular and immune correlates of TIM-3...
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Recherchemedicale.com › Diagnostic › Pronostic › Molecular and immune correlates of TIM-3...
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