Abstract 1342: Roles of mesenchymal-like tumour cells and myofibroblastic cancer-associated fibroblasts in progression and therapeutic response of clear-cell renal cell carcinoma

Abstract Purpose: Immune checkpoint inhibitors (ICI) represent the cornerstone for treatment of patients with metastatic clear-cell renal cell carcinoma (ccRCC). Despite a favourable response for a subset of patients, others present primary progressive disease highlighting the need to better understand plasticity of cancer cells and their crosstalk with the microenvironment to better predict therapeutic response and personalize treatment. Experimental design: We performed single-cell RNA sequencing on 56,421 cells from tumour and normal adjacent tissue of patients with ccRCC at different disease stages. Identification of cancer and microenvironment cell populations was validated by deconvolution analyses of public datasets and their localizations within tumours were determined by spatial transcriptomic analyses. We also assessed association of tumour and microenvironment populations with response of ICI treated patients using data from the BIONIKK clinical trial (NCT02960906). Results: We identify 46 cell populations including 5 tumour subpopulations characterized by distinct transcriptional signatures representing an epithelial to mesenchymal transition gradient as well as novel inflamed state. Deconvolution of the tumour and microenvironment signatures revealed strong correlation between mesenchymal-like ccRCC cancer cells and myofibroblastic cancer-associated fibroblasts (myCAFs) that associate with metastasis and tumour aggressiveness. Spatial transcriptomics revealed their co-localization and we identified therapeutically targetable ligand-receptor interactions underlying their crosstalk. Finally, we show that enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. Conclusions: We describe epithelial-mesenchymal plasticity of ccRCC cancer cells and identify potentially targetable pathways involved in tumour cell-myCAFs crosstalk opening the way for personalized treatment of ccRCC patients. Citation Format: Alexandra Helleux, Guillaume Davidson, Yann A. Vano, Véronique Lindner, Antonin Fattori, Marie Cerciat, Reza T. Elaidi, Virginie Verkarre, Cheng-Ming Sun, Christine Chevreau, Mostefa Bennamoun, Hervé Lang, Thibault Tricard, Wolf H. Fridman, Catherine Sautes-Fridman, Xiaoping Su, Damien Plassard, Céline Keime, Christelle Thibault-Carpentier, Philippe Barthelemy, Stéphane Oudard, Irwin Davidson, Gabriel G. Malouf. Roles of mesenchymal-like tumour cells and myofibroblastic cancer-associated fibroblasts in progression and therapeutic response of clear-cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1342.