CCL5-dependent mast cell infiltration into the tumor microenvironment in clear cell renal cell carcinoma patients

We investigated the mechanisms affecting tumor progression and survival outcomes in Polybromo-1-mutated (PBRM1^MUT) clear cell renal cell carcinoma (ccRCC) patients. PBRM1^MUT ccRCC tissues contained higher numbers of mast cells and lower numbers of CD8⁺ and CD4⁺ T cells than tissues from PBRM1^WT ccRCC patients. Hierarchical clustering, pathway enrichment and GSEA analyses demonstrated that PBRM1 mutations promote tumor progression by activating hypoxia inducible factor (HIF)-related signaling pathways and increasing expression of vascular endothelial growth factor family genes. PBRM1^MUT ccRCC tissues also show increased expression of C-C motif chemokine ligand 5 (CCL5). PBRM1-silenced ccRCC cells exhibited greater Matrigel tube formation and cell proliferation than controls. In addition, HMC-1 human mast cells exhibited CCL5-dependent in vitro migration on Transwell plates. High CCL5 expression in PBRM1^MUT ccRCC patients correlated with increased expression of genes encoding IFN-γ, IFN-α, IL-6, JAK-STAT3, TNF-α, and NF-ΚB. Moreover, high CCL5 expression was associated with poorer survival outcomes in ccRCC patients. These findings demonstrate that CCL5-dependent mast cell infiltration promotes immunosuppression within the tumor microenvironment, resulting in tumor progression and adverse survival outcomes in PBRM1^MUT ccRCC patients.