Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas.
DNA methylation
angiogenesis
biomarker
clear-cell renal cell carcinoma
epigenetic silencing
immune checkpoint inhibitors
tumor microenvironment
Journal
Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894
Informations de publication
Date de publication:
21 Nov 2023
21 Nov 2023
Historique:
received:
08
05
2023
revised:
21
07
2023
accepted:
19
10
2023
medline:
27
11
2023
pubmed:
16
11
2023
entrez:
15
11
2023
Statut:
ppublish
Résumé
The efficacy of immune checkpoint inhibitors varies in clear-cell renal cell carcinoma (ccRCC), with notable primary resistance among patients. Here, we integrate epigenetic (DNA methylation) and transcriptome data to identify a ccRCC subtype characterized by cancer-specific promoter hypermethylation and epigenetic silencing of Polycomb targets. We develop and validate an index of methylation-based epigenetic silencing (iMES) that predicts primary resistance to immune checkpoint inhibition (ICI) in the BIONIKK trial. High iMES is associated with VEGF pathway silencing, endothelial cell depletion, immune activation/suppression, EZH2 activation, BAP1/SETD2 deficiency, and resistance to ICI. Combination therapy with hypomethylating agents or tyrosine kinase inhibitors may benefit patients with high iMES. Intriguingly, tumors with low iMES exhibit increased endothelial cells and improved ICI response, suggesting the importance of angiogenesis in ICI treatment. We also develop a transcriptome-based analogous system for extended applicability of iMES. Our study underscores the interplay between epigenetic alterations and tumor microenvironment in determining immunotherapy response.
Identifiants
pubmed: 37967556
pii: S2666-3791(23)00481-0
doi: 10.1016/j.xcrm.2023.101287
pmc: PMC10694769
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
101287Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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