Faculty, Staff and Student Publications
Publication Date
11-21-2023
Journal
Cell Reports Medicine
Abstract
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.
Keywords
Humans, Carcinoma, Renal Cell, DNA Methylation, Kidney Neoplasms, Tumor Microenvironment, Endothelial Cells, Immunotherapy, DNA methylation, angiogenesis, biomarker, clear-cell renal cell carcinoma, epigenetic silencing, immune checkpoint inhibitors, tumor microenvironment
DOI
10.1016/j.xcrm.2023.101287
PMID
37967556
PMCID
PMC10694769
PubMedCentral® Posted Date
11-14-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons