A new link between cancer-associated fibroblasts and immunotherapy resistance in clear-cell kidney cancer
Immunotherapy is the first-line treatment for patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response in a sub-group of patients, others show progression from the outset to these treatments. In a study published in the journal Cancer Research, Professor Gabriel Maalouf and Irwin Davidson's team have highlighted the decisive contribution of a specialized population of cancer-associated fibroblasts, known as myofibroblasts, to resistance to immunotherapy.
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, accounting for 75% of all cases, with around 315,000 new patients worldwide every year. Immunotherapy is the first-line treatment for advanced-stage ccRCCs. However, a significant proportion of patients present primary resistance to immunotherapy, with tumor escape. The researchers therefore analyzed the composition of ccRCCs tumors and their microenvironment to understand how different cell populations contribute to immunotherapy resistance.
The researchers used single-cell transcriptomics to profile gene expression in 56,421 cells from patient ccRCCs and adjacent normal tissues. This approach enabled the identification of at least 46 different cell populations, including at least 5 tumor cell types forming a gradient from epithelial to mesenchymal program. Among these different populations, there is a strong association between mesenchymal tumor cells and a specialized population of cancer-associated fibroblasts known as myofibroblasts. Spatial transcriptomics experiments to localize the different cell populations within tumors have shown that myofibroblasts and tumor mesenchymal cells often localize together at the tumor invasion front at the interface with normal tissue. What's more, based on data from a national clinical trial called BIONNIK, researchers have shown that the presence of myofibroblasts in tumors is associated with patient resistance to immunotherapy and, more generally, with a poor prognosis.
The use of these new transcriptomics technologies has highlighted the plasticity of ccRCC tumor cells and their interactions with the tumor microenvironment. The results show for the first time the role of myofibroblasts in the aggressiveness of clear cell renal cell carcinoma, and identify them as key players in modulating the response to immunotherapy. This new knowledge should enable us to better identify patients who may develop resistance to immunotherapy, and thus personalize their treatment.
Model for ccRCC organization showing the presence of myofibroblasts (myCAFs) and mesenchymal ccRCC cells (ccRCC.mes) at the interface between tumor and normal tissue consisting mainly of proximal straight tubules (PST). Myofibroblasts and ccRCC.mes are also enriched in metastases. Thus, myofibroblasts contribute to both invasion of normal tissue and resistance to immunotherapy.
Image created with BioRender.
Credits: Alexandra Helleux, IGBMC Illkirch