ICOS DNA methylation regulates melanoma cell-intrinsic ICOS expression, is associated with melanoma differentiation, prognosis, and predicts response to immune checkpoint blockade.
Epigenetics
ICOS
ICOS DNA methylation
Immune checkpoint blockade
Melanoma
Predictive biomarker
Journal
Biomarker research
ISSN: 2050-7771
Titre abrégé: Biomark Res
Pays: England
ID NLM: 101607860
Informations de publication
Date de publication:
01 Jun 2023
01 Jun 2023
Historique:
received:
16
11
2022
accepted:
29
05
2023
medline:
1
6
2023
pubmed:
1
6
2023
entrez:
31
5
2023
Statut:
epublish
Résumé
Inducible T cell costimulator ICOS is an emerging target in immuno-oncology. The aim of this study was to investigate the epigenetic regulation of ICOS in melanoma by DNA methylation. We comprehensively investigate ICOS DNA methylation of specific CpG sites and expression pattern within the melanoma microenvironment with regard to immune correlates, differentiation, clinical outcomes, and immune checkpoint blockade (ICB) response. Our study revealed a sequence-contextual CpG methylation pattern consistent with an epigenetically regulated gene. We found a cell type-specific methylation pattern and locus-specific correlations and associations of CpG methylation with ICOS mRNA expression, immune infiltration, melanoma differentiation, prognosis, and response to ICB. High ICOS mRNA expression was identified as a surrogate for enriched immune cell infiltration and was associated with favorable overall survival (OS) in non-ICB-treated patients and predicted response and a prolonged progression-free survival (PFS) following ICB therapy initiation. ICOS hypomethylation, however, significantly correlated with poor OS in non-ICB patients but predicted higher response and prolonged PFS and OS in ICB-treated patients. Moreover, we observed cytoplasmic and sporadically nuclear tumor cell-intrinsic ICOS protein expression. Tumor cell-intrinsic ICOS protein and mRNA expression was inducible by pharmacological demethylation with decitabine. Our study identified ICOS DNA methylation and mRNA expression as promising prognostic and predictive biomarkers for immunotherapy in melanoma and points towards a hitherto undescribed role of ICOS in tumor cells.
Sections du résumé
BACKGROUND
BACKGROUND
Inducible T cell costimulator ICOS is an emerging target in immuno-oncology. The aim of this study was to investigate the epigenetic regulation of ICOS in melanoma by DNA methylation.
METHODS
METHODS
We comprehensively investigate ICOS DNA methylation of specific CpG sites and expression pattern within the melanoma microenvironment with regard to immune correlates, differentiation, clinical outcomes, and immune checkpoint blockade (ICB) response.
RESULTS
RESULTS
Our study revealed a sequence-contextual CpG methylation pattern consistent with an epigenetically regulated gene. We found a cell type-specific methylation pattern and locus-specific correlations and associations of CpG methylation with ICOS mRNA expression, immune infiltration, melanoma differentiation, prognosis, and response to ICB. High ICOS mRNA expression was identified as a surrogate for enriched immune cell infiltration and was associated with favorable overall survival (OS) in non-ICB-treated patients and predicted response and a prolonged progression-free survival (PFS) following ICB therapy initiation. ICOS hypomethylation, however, significantly correlated with poor OS in non-ICB patients but predicted higher response and prolonged PFS and OS in ICB-treated patients. Moreover, we observed cytoplasmic and sporadically nuclear tumor cell-intrinsic ICOS protein expression. Tumor cell-intrinsic ICOS protein and mRNA expression was inducible by pharmacological demethylation with decitabine.
CONCLUSION
CONCLUSIONS
Our study identified ICOS DNA methylation and mRNA expression as promising prognostic and predictive biomarkers for immunotherapy in melanoma and points towards a hitherto undescribed role of ICOS in tumor cells.
Identifiants
pubmed: 37259155
doi: 10.1186/s40364-023-00508-2
pii: 10.1186/s40364-023-00508-2
pmc: PMC10233860
doi:
Types de publication
Journal Article
Langues
eng
Pagination
56Subventions
Organisme : University Medical Center Bonn (UKB) BONFOR program
ID : 2021-1A-14
Organisme : University Medical Center Bonn (UKB) BONFOR program
ID : 2022-1A-08
Organisme : University Medical Center Bonn (UKB) BONFOR program
ID : 2022-4-18
Organisme : University Medical Center Bonn (UKB) BONFOR program
ID : 2020-2A-12
Organisme : German Society of Urology
ID : KIN1/FE-19
Organisme : German Cancer Aid
ID : 70113307
Organisme : Novartis MAYA Research Initiative 2021
ID : S2TAF-80
Informations de copyright
© 2023. The Author(s).
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