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

Fiche publication

Date publication

novembre 2023

Journal

Cell reports. Medicine

Auteurs

Membres identifiés du Cancéropôle Est :
Dr BARTHELEMY Philippe , Dr DAVIDSON Irwin , Pr LANG Hervé , Dr LINDNER Véronique , Pr MALOUF Gabriel

Tous les auteurs :
Lu X, Vano YA, Su X, Helleux A, Lindner V, Mouawad R, Spano JP, Rouprêt M, Compérat E, Verkarre V, Sun CM, Bennamoun M, Lang H, Barthelemy P, Cheng W, Xu L, Davidson I, Yan F, Fridman WH, Sautes-Fridman C, Oudard S, Malouf GG

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/37967556

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.