Immune checkpoint inhibitors have revolutionized the treatment of patients with clear-cell renal carcinomas (ccRCC). 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.
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 IL-6/JAK/STAT3 pathways, and displayed a tumor microenvironment characterized by both immune activation and suppressive populations, fibroblasts 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 immune checkpoint inhibitors that may pave the way to better personalizing patients' treatments.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Nov 14 [Epub ahead of print]
Xiaofan Lu, Yann Vano, Alexandra Helleux, Xiaoping Su, Veronique Lindner, Guillaume Davidson, Roger Mouawad, Jean-Philippe Spano, Morgan Roupret, 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
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France., Hopital Européen Georges Pompidou, APHP.Centre, Paris, FRANCE, France., IGBMC, Strasbourg, France., The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Strasbourg University Hospital, Strasbourg, France., University Pierre and Marie Curie, Paris, France., Groupe Hospitalier Pitié-Salpêtrière, Paris, France., Pitie Salpétrière, Paris, France., Association pour la Recherche de Thérapeutiques Innovantes en Cancérologie, Paris, France., Sorbonne University, France., Hopital Européen Georges Pompidou, Paris, FRANCE, France., Centre de Recherche des Cordeliers, Paris, France., University Institute of Cancerology, Toulouse, France., Institute Mutualiste Montsouris, France., New Hospital of Strasbourg, Strasbourg, France., CHU Strasbourg, France., China Pharmaceutical University, Nanjing, Jingsu, China., China Pharmaceutical University, Nanjing, Jiangsu, China., University Paris-Descartes, Paris, France., Centre de Recherche des Cordeliers, Inserm UMRS 1138, Paris, France., Hopital Européen Georges Pompidou, Paris, Ile de France, France., Institut de Cancérologie de Strasbourg, Strasbourg, France.