Geospatial Cellular Distribution of Cancer-Associated Fibroblasts Significantly Impacts Clinical Outcomes in Metastatic Clear Cell Renal Cell Carcinoma

Cancer-associated fibroblasts (CAF) are highly prevalent cells in the tumor microenvironment clear cell renal carcinoma (ccRCC). CAFs exhibit a pro-tumor effect vitro and have been implicated proliferation, metastasis, treatment resistance. Our objective is to analyze geospatial distribution of with proliferating apoptotic ccRCC determine associations survival systemic treatment. Pre-treatment primary samples were collected from 96 patients metastatic ccRCC. Three adjacent slices obtained 2 tumor-core regions interest (ROI) per patient, immunohistochemistry (IHC) staining was performed for αSMA, Ki-67, caspase-3 detect CAFs, cells, respectively. H-scores cellular density generated each marker. ROIs aligned, spatial point patterns generated, which then used perform analyses using normalized Ripley’s K function at radius 25 μm (nK(25)). The an optimal cut-point method, maximizing log-rank statistic, stratify IHC-derived metrics into high low groups. Multivariable Cox regression accounting age International Metastatic RCC Database Consortium (IMDC) risk category. Survival outcomes included overall (OS) date diagnosis, OS immunotherapy initiation (OS-IT), targeted therapy (OS-TT). Therapy resistance defined as progression-free (PFS) <6 months, response PFS >9 months. exhibited higher clustering Ki-67+ than caspase-3+ (nK(25): Ki-67 1.19; 1.05; p = 0.04). median nearest neighbor (NN) distance shorter compared (15 vs. 37 μm, respectively; < 0.001). demonstrated that both H-score associated worse OS, OS-IT, OS-TT. Regarding αSMA+CAFs, only For caspase-3+, Patients whose tumors resistant (TT) had those who TT responses. Overall, this ex vivo analysis CAF suggests close proximity potentiates resulting