American Association for Cancer Research
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Figure S2 from An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas

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journal contribution
posted on 2023-04-01, 00:04 authored by Xiaofan Lu, Yann Vano, Alexandra Helleux, Xiaoping Su, Véronique Lindner, Guillaume Davidson, Roger Mouawad, Jean-Philippe Spano, Morgan Rouprêt, Reza Elaidi, Eva Compérat, Virginie Verkarre, Chengming Sun, Christine Chevreau, Mostefa Bennamoun, Hervé Lang, Thibault Tricard, Wenxuan Cheng, Li Xu, Irwin Davidson, Fangrong Yan, Wolf Herman Fridman, Catherine Sautes-Fridman, Stéphane Oudard, Gabriel G. Malouf

Figure S2. Focal copy number deletion identified by the GISTIC algorithm for a) 𝑇𝐸𝐷+ and b) 𝑇𝐸𝐷−, respectively, in the TCGA-KIRC cohort.



Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown. We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib. A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial–mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a 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. We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients’ treatments.

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