Molecular, clinicopathological, and immune correlates of LAG3 promoter DNA methylation in melanoma.

Antigens, CD / genetics Biomarkers, Tumor Cell Line, Tumor DNA Methylation Epigenesis, Genetic Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Immunotherapy Kaplan-Meier Estimate Lymphocytes, Tumor-Infiltrating / immunology Melanoma / etiology Molecular Targeted Therapy Neoplasm Grading Neoplasm Staging Prognosis Promoter Regions, Genetic Treatment Outcome Tumor Microenvironment Lymphocyte Activation Gene 3 Protein
DNA Methylation Immunotherapy LAG3 Melanoma Predictive Biomarker

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
Sep 2020
Historique:
received: 19 02 2020
revised: 03 08 2020
accepted: 04 08 2020
pubmed: 30 8 2020
medline: 29 6 2021
entrez: 30 8 2020
Statut: ppublish

Résumé

The co-receptor lymphocyte-activation gene-3 (LAG3, LAG-3, CD223) is a potential target for immune checkpoint inhibition immunotherapies. However, little is known about the biological and clinical significance of LAG3 DNA methylation in melanoma and its microenvironment. We evaluated LAG3 promoter and gene body methylation in a cohort of N = 470 melanoma patients obtained from The Cancer Genome Atlas (TCGA cohort), an independent cohort of N = 120 patients from the University Hospital Bonn, and in subsets of peripheral blood leukocytes, melanocytes, and melanoma cell lines. We validated the association of LAG3 methylation with mRNA expression in vitro in the melanoma cell line A375 treated with the hypomethylating agent 5-azacytidine and stimulated with interferon-γ. Finally, we investigated correlations between LAG3 methylation and progression-free survival in patients treated with immune checkpoint blockade (ICB cohort, N = 118). Depending on the analysed locus (promoter, gene body) we found region-dependent significant LAG3 methylation differences between monocytes, B cells, CD8 Our study points towards an epigenetic regulation of LAG3 via promoter methylation and suggests a prognostic and predictive significance of LAG3 methylation in melanoma. Our results give insight in the tumor cell-intrinsic transcriptional regulation of LAG3 in melanoma. In perspective, our results might pave the way for investigating LAG3 methylation as a predictive biomarker for response to anti-LAG3 immune checkpoint blockage. A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Sections du résumé

BACKGROUND BACKGROUND
The co-receptor lymphocyte-activation gene-3 (LAG3, LAG-3, CD223) is a potential target for immune checkpoint inhibition immunotherapies. However, little is known about the biological and clinical significance of LAG3 DNA methylation in melanoma and its microenvironment.
METHODS METHODS
We evaluated LAG3 promoter and gene body methylation in a cohort of N = 470 melanoma patients obtained from The Cancer Genome Atlas (TCGA cohort), an independent cohort of N = 120 patients from the University Hospital Bonn, and in subsets of peripheral blood leukocytes, melanocytes, and melanoma cell lines. We validated the association of LAG3 methylation with mRNA expression in vitro in the melanoma cell line A375 treated with the hypomethylating agent 5-azacytidine and stimulated with interferon-γ. Finally, we investigated correlations between LAG3 methylation and progression-free survival in patients treated with immune checkpoint blockade (ICB cohort, N = 118).
FINDINGS RESULTS
Depending on the analysed locus (promoter, gene body) we found region-dependent significant LAG3 methylation differences between monocytes, B cells, CD8
INTERPRETATION CONCLUSIONS
Our study points towards an epigenetic regulation of LAG3 via promoter methylation and suggests a prognostic and predictive significance of LAG3 methylation in melanoma. Our results give insight in the tumor cell-intrinsic transcriptional regulation of LAG3 in melanoma. In perspective, our results might pave the way for investigating LAG3 methylation as a predictive biomarker for response to anti-LAG3 immune checkpoint blockage.
FUNDING BACKGROUND
A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Identifiants

DOI: 10.1016/j.ebiom.2020.102962 PMID: 32861198 PMC: PMC7475111
pubmed: 32861198
pii: S2352-3964(20)30338-8
doi: 10.1016/j.ebiom.2020.102962
pmc: PMC7475111
pii:
doi:

Substances chimiques

Antigens, CD 0
Biomarkers, Tumor 0
Lymphocyte Activation Gene 3 Protein 0
Lag3 protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

102962

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

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Auteurs

Anne Fröhlich (A)

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

Judith Sirokay (J)

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

Simon Fietz (S)

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

Timo J Vogt (TJ)

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

Jörn 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.

Mike Florin (M)

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

Pia Kuster (P)

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

Gonzalo Saavedra (G)

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

Susana Ramírez Valladolid (SR)

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

Friederike Hoffmann (F)

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

Lukas Flatz (L)

Institute of Immunobiology, Kantonsspital St Gallen, St Gallen, Switzerland.; Department of Oncology and Haematology, Kantonsspital St Gallen, St Gallen, Switzerland; Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; Department of Dermatology and Allergology, Kantonsspital St Gallen, St Gallen, Switzerland.

Sandra S Ring (SS)

Institute of Immunobiology, Kantonsspital St Gallen, St Gallen, Switzerland.; Microbiology and Immunology PhD Program, University of Zurich, Zurich, Switzerland.

Carsten Golletz (C)

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

Torsten Pietsch (T)

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

Sebastian Strieth (S)

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

Peter Brossart (P)

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

Gerrit H Gielen (GH)

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

Glen Kristiansen (G)

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

Friedrich Bootz (F)

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

Jennifer Landsberg (J)

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

Dimo Dietrich (D)

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Electronic address: dimo.dietrich@gmail.com.

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