An enhancer demethylator phenotype tightly associated with immune exhaustion and resistance to immune checkpoint inhibitors in clear-cell renal cell carcinomas

Abstract Immune checkpoint inhibitors have revolutionized the treatment of patients with clear-cell renal carcinomas. Although, analyses of transcriptome, genetic alterations, and the tumor microenvironment have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown. Herein, we investigated the methylome of six clear-cell renal cell carcinomas cohorts and discovered a group of tumors with enhancer demethylation, namely \(TED\). \(TED\) was associated with tumors with sarcomatoid differentiation and poor clinical outcome. \(TED\) harbored TET1 and JAK3 promoter demethylation, activated the gene expression signature of epithelial-mesenchymal transition and IL-6/JAK/STAT3 pathways, and displayed a tumor microenvironment characterized by immune exhaustion, fibroblasts infiltration, and endothelial depletion. In addition, \(TED\) was the only predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, \(TED\) was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort. In conclusion, we report on the discovery of a novel epigenetic phenotype associated with resistance to immune checkpoint inhibitors that may pave the way to better personalizing patients’ treatments.