An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas - Archive ouverte HAL Access content directly
Journal Articles Clinical Cancer Research Year : 2023

An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas

Xiaofan Lu
  • Function : Author
Yann Vano
  • Function : Author
Xiaoping Su
  • Function : Author
Veronique Lindner
  • Function : Author
  • PersonId : 1065503
Guillaume Davidson
  • Function : Author
Roger Mouawad
  • Function : Author
Jean-Philippe Spano
  • Function : Author
Morgan Rouprêt
  • Function : Author
Reza Elaidi
  • Function : Author
Eva Compérat
  • Function : Author
Virginie Verkarre
  • Function : Author
Christine Chevreau
  • Function : Author
Mostefa Bennamoun
  • Function : Author
Thibault Tricard
  • Function : Author
Wenxuan Cheng
  • Function : Author
Li Xu
  • Function : Author
Fangrong Yan
  • Function : Author
Stéphane Oudard
  • Function : Author

Abstract

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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. See related commentary by Zhou and Kim, p. 1170.

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Cancer

Dates and versions

hal-04458623 , version 1 (14-02-2024)

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Xiaofan Lu, Yann Vano, Alexandra Helleux, Xiaoping Su, Veronique Lindner, et al.. An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas. Clinical Cancer Research, 2023, 29 (7), pp.1279-1291. ⟨10.1158/1078-0432.CCR-22-2133⟩. ⟨hal-04458623⟩
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