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

• Published in: Aging (Albany, NY.) Vol. 12; no. 21; pp. 21809 - 21836
• Main Authors: Liu, Tianjie, Xia, Qing, Zhang, Haibao, Wang, Zixi, Yang, Wenjie, Gu, Xiaoyun, Hou, Tao, Chen, Yule, Pei, Xinqi, Zhu, Guodong, He, Dalin, Li, Lei, Xu, Shan
• Format: Journal Article
• Language: English
• Published: United States Impact Journals 11-11-2020
• Subjects: Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CCL5 - genetics; Chemokine CCL5 - metabolism; Coculture Techniques; Databases, Genetic; Disease Progression; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Kidney Neoplasms - genetics; Kidney Neoplasms - immunology; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Mast Cells - immunology; Mast Cells - metabolism; Mutation; Neovascularization, Pathologic; Prognosis; Research Paper; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptome; Tumor Escape; Tumor Microenvironment; mast cell; PBRM1; RCC; tumor microenvironment; CCL5
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.103999

We investigated the mechanisms affecting tumor progression and survival outcomes in
-mutated (
) clear cell renal cell carcinoma (ccRCC) patients.
ccRCC tissues contained higher numbers of mast cells and lower numbers of CD8
and CD4
T cells than tissues from
ccRCC patients. Hierarchical clustering, pathway enrichment and GSEA analyses demonstrated that
mutations promote tumor progression by activating hypoxia inducible factor (HIF)-related signaling pathways and increasing expression of vascular endothelial growth factor family genes.
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
migration on Transwell plates. High CCL5 expression in
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
ccRCC patients.