Clear cell renal cell carcinoma is the most common subtype of kidney cancer and accounts for more than 3% of all cancers. At the time of diagnosis, approximately 30% of cases are already metastatic, with a poor prognosis and no durable benefit from traditional oncological treatments such as chemotherapy and radiotherapy. The advent of targeted therapies directed against angiogenesis and signal transduction pathways, such as sunitinib, temsirolimus, and pazopanib, has improved clinical benefit and survival. Nevertheless, these treatments frequently encounter acquired resistance, often through the activation of alternative pathways, and the response is only short-lived. More recently, immune checkpoint inhibitors have demonstrated significant antitumor activity in the first-line setting, but benefit only a small fraction of patients, at the cost of adverse effects and high expenses. A major obstacle to the development of new strategies lies in the lack of preclinical models capable of reliably predicting drug efficacy and guiding each patient toward the appropriate protocol.
To address this need, the authors compared different three-dimensional culture models of clear cell renal cell carcinoma and highlighted the value of ex vivo treatment of freshly surgically resected human tumor slices. Existing approaches indeed have limitations: two-dimensional cell lines select for the most robust cells and poorly reproduce tumor heterogeneity; organoids do not model the interactions between cancer, immune, and endothelial cells; and patient-derived xenografts are restricted in their use by their low engraftment rates, lengthy timelines, high costs, and progressive drift from the original tumor. By contrast, the model described relies on 300 µm precision-cut tissue slices, prepared with a vibratome, placed on culture membranes, and maintained for up to 96 hours, with two distinct samples per tumor treated with the inhibitors under study. The tumors originated from patients who had undergone partial or total nephrectomy, and slice viability was assessed by live/dead cell staining, complemented by immunohistochemical analyses.
The central advantage of this method lies in the preservation of tumor architecture, and thus of the spatial relationships between the tumor, infiltrating lymphocytes, and stromal components—all elements on which clinical outcome closely depends. The authors consider that acute treatment of tumor slices could serve as a companion diagnostic tool in the management of clear cell renal cell carcinoma, as well as a platform for the development of new drugs. Consistent with the key role of the immune infiltrate in this disease, this strategy warrants further investigation to confirm the correlations between drug sensitivity, the degree of tumor vascularization, and infiltrating immune populations, and could ultimately contribute to personalized immunotherapy.