Immune checkpoint inhibitors (ICI) represent the cornerstone for treatment of patients with metastatic clear-cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease highlighting the need to precisely understand plasticity of cancer cells and their crosstalk with the microenvironment to better predict therapeutic response and personalize treatment.
Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial to mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public datasets and in data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAFs), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. This data highlights the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance.
Cancer research. 2023 Jun 19 [Epub ahead of print]
Guillaume Davidson, Alexandra Helleux, Yann A Vano, Véronique Lindner, Antonin Fattori, Marie Cerciat, Reza Thierry Elaidi, Virginie Verkarre, Cheng-Ming Sun, Christine Chevreau, Mostefa Bennamoun, Hervé Lang, Thibault Tricard, Wolf Herman Fridman, Catherine Sautes-Fridman, Xiaoping Su, Damien Plassard, Celine Keime, Christelle Thibault-Carpentier, Philippe Barthélémy, Stéphane Marie Oudard, Irwin Davidson, Gabriel G Malouf
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France., IGBMC, Strasbourg, France., Hopital Européen Georges Pompidou, APHP.Centre, Paris, FRANCE, France., Strasbourg University Hospital, Strasbourg, France., IGBMC, Illkirch, France., Association pour la Recherche de Thérapeutiques Innovantes en Cancérologie, Paris, 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, Strasbourg, France., University Paris-Descartes, Paris, France., Centre de Recherche des Cordeliers, Inserm UMRS 1138, Paris, France., The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., IGBMC, France., IGBMC - CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France., Hôpitaux Universitaires de Strasbourg, Strasbourg, France., Hopital Européen Georges Pompidou, Paris, Ile de France, France., Institut de Cancérologie de Strasbourg, Strasbourg, France.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37335139