[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-381908-105":59,"doc-detail-381908-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","silencing-of-genes-by-promoter-hypermethylation-shapes-tumor-microenvironment-and-resistance-to-immunotherapy-in-clear-cell-renal-cell-carcinomas","Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas","","Immune checkpoint inhibitor efficacy varies in clear-cell renal cell carcinoma (ccRCC), with primary resistance limiting durable benefit. The study integrates DNA methylation and transcriptome profiles to define a ccRCC subtype marked by cancer-specific promoter hypermethylation and epigenetic silencing of Polycomb targets. An index of methylation-based epigenetic silencing (iMES) is developed and validated to predict resistance to ICI in the BIONIKK trial. High iMES links to VEGF pathway silencing, endothelial depletion, immune activation/suppression dynamics, EZH2 activation, BAP1/SETD2 loss, and potential benefit from combination therapies.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/silencing-of-genes-by-promoter-hypermethylation-shapes-tumor-microenvironment-and-resistance-to-immunotherapy-in-clear-cell-renal-cell-carcinomas/381908/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/silencing-of-genes-by-promoter-hypermethylation-shapes-tumor-microenvironment-and-resistance-to-immunotherapy-in-clear-cell-renal-cell-carcinomas/381908.png","ImageObject",300,407,{"name":92,"@type":93},"Blitz","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-26","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What does the iMES signature predict in clear-cell renal cell carcinoma?","Question",{"text":112,"@type":113},"iMES predicts primary resistance to immune checkpoint inhibition in ccRCC, based on methylation-based epigenetic silencing features.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How is iMES linked to the tumor microenvironment?",{"text":117,"@type":113},"High iMES is associated with VEGF pathway silencing, endothelial cell depletion, and immune activation/suppression patterns that collectively shape immunotherapy response.",{"name":119,"@type":110,"acceptedAnswer":120},"What biological factors are associated with elevated iMES?",{"text":121,"@type":113},"Elevated iMES correlates with EZH2 activation and BAP1/SETD2 deficiency, supporting an epigenetic mechanism underlying immunotherapy resistance.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},381908,1790320005,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":26},24464137899374,"https://us-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Article  \nSilencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas  \nGraphical abstract  \nHighlights  \nd Gene silencing influences both ccRCC aggressiveness and microenvironment  \nd A methylation index (iMES) reliably predicts ICI treatment outcomes in ccRCC  \nd Elevated iMES correlates with EZH2 activation and BAP1/ SETD2 deficiency  \nd iMES and angiogenesis jointly impact response to immunotherapy in ccRCC  \nAuthors  \nXiaofan Lu, Yann-Alexandre Vano, Xiaoping Su, ...,  \nCatherine Sautes-Fridman, St´ephane Oudard, Gabriel G. Malouf  \nCorrespondence  \n[maloufg@igbmc.fr](maloufg@igbmc.fr)  \nIn brief  \nLu et al. develop an index of methylationbased epigenetic silencing (iMES) signature and unveils its potential to predict immunotherapy outcomes in clear-cell renal cell carcinoma (ccRCC), unlocking the intricate relationship between the tumor microenvironment and promoter methylation. Intriguingly, endothelial cell depletion corresponds to VEGF pathway methylation, proposing a link between iMES, angiogenesis, and immunotherapy response in ccRCC patients.  \nLu et al., 2023, Cell Reports Medicine 4, 101287 November 21, 2023 ª 2023 The Authors.  \n[https://doi.org/10.1016/j.xcrm.2023.101287](https://doi.org/10.1016/j.xcrm.2023.101287)  \nll  \nll  \nOPEN ACCESS  \nArticle  \nSilencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas  \nXiaofan Lu,1,16 Yann-Alexandre Vano,2,3,16 Xiaoping Su,4,16 Alexandra Helleux,1 V´eronique Lindner,5 Roger Mouawad,6 Jean-Philippe Spano,6 Morgan Roupr^et,7 Eva Comp´erat,8 Virginie Verkarre,9 Cheng-Ming Sun,3 Mostefa Bennamoun,10 Herv´e Lang,11 Philippe Barthelemy,12 Wenxuan Cheng,13 Li Xu,13 Irwin Davidson,1 Fangrong Yan,13 Wolf Herv´e Fridman,3 Catherine Sautes-Fridman,3 St´ephane Oudard,3,15,17 and Gabriel G. Malouf1,14,15,17,18,*  \n1Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA, 67400 Illkirch, France  \n2Department of Medical Oncology, H^opital Europ´een Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP, Universit´e Paris Cit´e , Paris, France  \n3Centre de Recherche Cordeliers, INSERM 1138, Universit´e de Paris Cit´e, Sorbonne Universit´e, Equipe labellis´ee Ligue contre le Cancer, 75006 Paris, France  \n4Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA  \n5Department of Pathology, Strasbourg University Hospital, Strasbourg, France  \n6Department of Medical Oncology, Sorbonne University, AP-HP, H^opital Piti´e-Salp^etri`ere, Paris, France  \n7Sorbonne University, GRC 5 P, UKredictive Onco-Uro, AP-HP, Urology, Piti´e-Salp^etri`ere Hospital, 75013 Paris, France  \n8Department of Pathology, Sorbonne University, AP-HP, H^opital Tenon, Paris, France  \n9Department of Pathology, H^opital Europ´een Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP, Universit´e Paris Cit´e, Paris, France  \n10Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France  \n11Department of Urology, Strasbourg University Hospital, Strasbourg, France  \n12Department of Medical Oncology, Strasbourg University, Institut de Canc´erologie de Strasbourg, Strasbourg, France  \n13Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, P. R. China  \n14Department of Medical Oncology, Strasbourg University, Institut de Canc´erologie de Strasbourg, Strasbourg, France  \n15Senior author  \n16These authors contributed equally  \n17These authors contributed equally  \n18Lead contact  \n*[Correspondence:](Correspondence: maloufg@igbmc.fr)[ maloufg@igbmc.fr](Correspondence: maloufg@igbmc.fr)[ ](Correspondence: maloufg@igbmc.fr)[https://doi.org/10.1016/j.xcrm.2023.101287](https://doi.org/10.1016/j.xcrm.2023.101287)  \nSUMMARY  \nThe efficacy of immune checkpoint inhibi","cbCaif2322E9vbhV","https://ap.wps.com/l/cbCaif2322E9vbhV","pdf",10160867,24,"English","# Graphical abstract and highlights\n## Molecular index iMES and prediction of ICI outcomes\n## Mechanistic links to EZH2, BAP1/SETD2 and VEGF/angiogenesis\n# Summary\n# Introduction","[{\"question\":\"What does the iMES signature predict in clear-cell renal cell carcinoma?\",\"answer\":\"iMES predicts primary resistance to immune checkpoint inhibition in ccRCC, based on methylation-based epigenetic silencing features.\"},{\"question\":\"How is iMES linked to the tumor microenvironment?\",\"answer\":\"High iMES is associated with VEGF pathway silencing, endothelial cell depletion, and immune activation/suppression patterns that collectively shape immunotherapy response.\"},{\"question\":\"What biological factors are associated with elevated iMES?\",\"answer\":\"Elevated iMES correlates with EZH2 activation and BAP1/SETD2 deficiency, supporting an epigenetic mechanism underlying immunotherapy resistance.\"}]","Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas | PDF",1790247707]