Academic Journal
An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas
| العنوان: | An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas |
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| المؤلفون: | Lu, Xiaofan, Vano, Yann, Helleux, Alexandra, Su, Xiaoping, Lindner, Veronique, Davidson, Guillaume, Mouawad, Roger, Spano, Jean-Philippe, Rouprêt, Morgan, Elaidi, Reza, Compérat, Eva, Verkarre, Virginie, Sun, Chengming, Chevreau, Christine, Bennamoun, Mostefa, Lang, Hervé, Tricard, Thibault, Cheng, Wenxuan, Xu, Li, Davidson, Irwin, Yan, Fangrong, Fridman, Wolf Herman, Sautes-Fridman, Catherine, Oudard, Stéphane, Malouf, Gabriel G. |
| المساهمون: | Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Centre Paul Strauss (CRLCC Paul Strauss), UNICANCER-UNICANCER-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| المصدر: | ISSN: 1078-0432. |
| بيانات النشر: | CCSD American Association for Cancer Research |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | [SDV.CAN]Life Sciences [q-bio]/Cancer |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1158/1078-0432.CCR-22-2133 |
| الاتاحة: | https://hal.science/hal-04458623 https://doi.org/10.1158/1078-0432.CCR-22-2133 |
| رقم الانضمام: | edsbas.BC9CD5DD |
| قاعدة البيانات: | BASE |
| DOI: | 10.1158/1078-0432.CCR-22-2133 |
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