Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas.

Autor:	Lu X; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400 Illkirch, France., Vano YA; Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP, Université Paris Cité, Paris, France; Centre de Recherche Cordeliers, INSERM 1138, Université de Paris Cité, Sorbonne Université, Equipe labellisée Ligue contre le Cancer, 75006 Paris, France., Su X; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Helleux A; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400 Illkirch, France., Lindner V; Department of Pathology, Strasbourg University Hospital, Strasbourg, France., Mouawad R; Department of Medical Oncology, Sorbonne University, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France., Spano JP; Department of Medical Oncology, Sorbonne University, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France., Rouprêt M; Sorbonne University, GRC 5 P, UKredictive Onco-Uro, AP-HP, Urology, Pitié-Salpêtrière Hospital, 75013 Paris, France., Compérat E; Department of Pathology, Sorbonne University, AP-HP, Hôpital Tenon, Paris, France., Verkarre V; Department of Pathology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP, Université Paris Cité, Paris, France., Sun CM; Centre de Recherche Cordeliers, INSERM 1138, Université de Paris Cité, Sorbonne Université, Equipe labellisée Ligue contre le Cancer, 75006 Paris, France., Bennamoun M; Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France., Lang H; Department of Urology, Strasbourg University Hospital, Strasbourg, France., Barthelemy P; Department of Medical Oncology, Strasbourg University, Institut de Cancérologie de Strasbourg, Strasbourg, France., Cheng W; Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, P.R. China., Xu L; Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, P.R. China., Davidson I; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400 Illkirch, France., Yan F; Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, P.R. China., Fridman WH; Centre de Recherche Cordeliers, INSERM 1138, Université de Paris Cité, Sorbonne Université, Equipe labellisée Ligue contre le Cancer, 75006 Paris, France., Sautes-Fridman C; Centre de Recherche Cordeliers, INSERM 1138, Université de Paris Cité, Sorbonne Université, Equipe labellisée Ligue contre le Cancer, 75006 Paris, France., Oudard S; Centre de Recherche Cordeliers, INSERM 1138, Université de Paris Cité, Sorbonne Université, Equipe labellisée Ligue contre le Cancer, 75006 Paris, France., Malouf GG; Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400 Illkirch, France; Department of Medical Oncology, Strasbourg University, Institut de Cancérologie de Strasbourg, Strasbourg, France. Electronic address: maloufg@igbmc.fr.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2023 Nov 21; Vol. 4 (11), pp. 101287. Date of Electronic Publication: 2023 Nov 14.
DOI:	10.1016/j.xcrm.2023.101287
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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