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.
Cell reports. Medicine. 2023 Nov 08 [Epub ahead of print]
Xiaofan Lu, Yann-Alexandre Vano, Xiaoping Su, Alexandra Helleux, Véronique Lindner, Roger Mouawad, Jean-Philippe Spano, Morgan Rouprêt, Eva Compérat, Virginie Verkarre, Cheng-Ming Sun, Mostefa Bennamoun, Hervé Lang, Philippe Barthelemy, Wenxuan Cheng, Li Xu, Irwin Davidson, Fangrong Yan, Wolf Hervé Fridman, Catherine Sautes-Fridman, Stéphane Oudard, Gabriel G Malouf
Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400 Illkirch, France., 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., Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Pathology, Strasbourg University Hospital, Strasbourg, France., Department of Medical Oncology, Sorbonne University, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France., Sorbonne University, GRC 5 P, UKredictive Onco-Uro, AP-HP, Urology, Pitié-Salpêtrière Hospital, 75013 Paris, France., Department of Pathology, Sorbonne University, AP-HP, Hôpital Tenon, Paris, France., Department of Pathology, 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., Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France., Department of Urology, Strasbourg University Hospital, Strasbourg, France., Department of Medical Oncology, Strasbourg University, Institut de Cancérologie de Strasbourg, Strasbourg, France., Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, P.R. China., 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: .