Research Paper Volume 12, Issue 21 pp 21809—21836
CCL5-dependent mast cell infiltration into the tumor microenvironment in clear cell renal cell carcinoma patients
- 1 Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, P.R. China
- 2 Oncology Research Laboratory, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an 710061, Shaanxi, P.R. China
- 3 Key Laboratory for Tumor Precision Medicine of Shaanxi Province, Xi’an Jiaotong University, Xi’an 710061, Shaanxi, P.R. China
- 4 Department of Oncology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai 200127, P.R. China
- 5 Shaanxi Health Information Center, Health Commission of Shaanxi Province, Xi’an 710061, Shaanxi, P.R. China
Received: February 5, 2020 Accepted: August 14, 2020 Published: November 11, 2020https://doi.org/10.18632/aging.103999
How to Cite
Copyright: © 2020 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
We investigated the mechanisms affecting tumor progression and survival outcomes in Polybromo-1-mutated (PBRM1MUT) clear cell renal cell carcinoma (ccRCC) patients. PBRM1MUT ccRCC tissues contained higher numbers of mast cells and lower numbers of CD8+ and CD4+ T cells than tissues from PBRM1WT 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. PBRM1MUT 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 PBRM1MUT 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 PBRM1MUT ccRCC patients.