Mesenchymal-like tumor cells and myofibroblastic cancer-associated fibroblasts are associated with progression and immunotherapy response of clear-cell renal cell carcinoma

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.