Clinical impact of intraepithelial versus stromal immune cells in kidney cancer

Although renal cell carcinoma (RCC), has become an important target for immune checkpoint therapies, the role of specific immune cell populations and checkpoint expression within its tumor microenvironment remains poorly understood. To learn more on the role of different immune cell populations and their expression of checkpoint proteins, we analyzed a tissue microarray containing 646 RCC samples using a 14-marker multiplex immunohistochemistry approach. Immune cell composition, checkpoint expression, and spatial distribution (stromal vs. intraepithelial) were quantified across 55 spatial immune parameters and evaluated for associations with clinicopathological features. With respect to individual cell types, high densities of FOXP3⁺ regulatory T-cells (Tregs) were significantly associated with advanced pT stage (p < 0.001), whereas other cell types or overall inflammatory infiltration showed no such association. Increased immune infiltration - specifically CD3⁺ and CD4⁺ T-cells - correlated with nodal metastasis (p < 0.05). Both associations were predominantly driven by stromal rather than intraepithelial immune cells. The expression of several checkpoint proteins in multiple cell types was associated with unfavorable tumor phenotype. Higher PD-1 expression on CD4⁺ (p < 0.001) and CD8⁺ T-cells (p = 0.03) and higher TIM-3 expression on FOXP3⁺ T-cells (p = 0.04) and CD11c⁺ dendritic cells (p = 0.04) were associated with advanced pT stage. High levels of PD-L1 expression on macrophages (p = 0.008), CTLA-4 expression on CD4⁺ (p = 0.04) and CD8⁺ (p = 0.005) T-cells, TIM-3 expression on FOXP3⁺ T-cells (p = 0.04), and PD-1 expression on CD4⁺ T-cells (p = 0.04) were linked to nodal metastasis. These immune checkpoint associations were likewise predominantly stromal in nature. It is concluded, that Immune cell composition and checkpoint pathway activity correlate with tumor progression and metastatic behavior in kidney cancer. These clinically relevant interactions arise primarily in the stromal compartment, highlighting the stroma as a key immune regulatory niche within the tumor microenvironment of kidney cancer.