TY - JOUR
T1 - Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas
AU - Lu, Xiaofan
AU - Vano, Yann Alexandre
AU - Su, Xiaoping
AU - Helleux, Alexandra
AU - Lindner, Véronique
AU - Mouawad, Roger
AU - Spano, Jean Philippe
AU - Rouprêt, Morgan
AU - Compérat, Eva
AU - Verkarre, Virginie
AU - Sun, Cheng Ming
AU - Bennamoun, Mostefa
AU - Lang, Hervé
AU - Barthelemy, Philippe
AU - Cheng, Wenxuan
AU - Xu, Li
AU - Davidson, Irwin
AU - Yan, Fangrong
AU - Fridman, Wolf Hervé
AU - Sautes-Fridman, Catherine
AU - Oudard, Stéphane
AU - Malouf, Gabriel G.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/11/21
Y1 - 2023/11/21
N2 - 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.
AB - 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.
KW - DNA methylation
KW - angiogenesis
KW - biomarker
KW - clear-cell renal cell carcinoma
KW - epigenetic silencing
KW - immune checkpoint inhibitors
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85177865487&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85177865487&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2023.101287
DO - 10.1016/j.xcrm.2023.101287
M3 - Article
C2 - 37967556
AN - SCOPUS:85177865487
SN - 2666-3791
VL - 4
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 11
M1 - 101287
ER -