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, 2020
https://doi.org/10.18632/aging.103999How 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.
Abstract
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.
Abbreviations
PBRM1: Polybromo-1; RCC: renal cell carcinoma; ccRCC: clear-cell RCC; CCL5: C-C motif chemokine ligand 5; IL-6: interleukin-6; JAK: Janus kinase-signal transducers; STAT3: signal transducer and activator of transcription 3; VHL: Von Hippel-Lindau; HIF: hypoxia inducible factor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; mTOR: mammalian target of rapamycin; TME: tumor microenvironment; BAF180: BRG1-associated factor 180; bFGF: basic fibroblast growth factor; ANG-1: Angiopoietin-1; IL-5: Interleukin 5; MHC II: major histocompatibility complex, class II; TNF-α: tumor necrosis factor alpha; SCF: stem cell factor; TCGA: the cancer genome atlas; GEO: gene expression omnibus; VST: variance stabilizing transformation; PBRM1WT: PBRM1 wild type; PBRM1MUT: PBRM1 mutation; VHLWT: VHL wild type; VHLMUT: VHL mutation; KIRC: kidney renal clear cell carcinoma; RMA: robust multiarray average; WGCNA: weighted correlation network analysis; DEGs: Differentially expressed genes; KEGG: Kyoto Encyclopedia of Genes and Genomes; IFN-γ: interferon-gamma; SFM: serum-free medium; CM: conditioned media; SETD2: SET domain containing 2; BAP1: BRCA1 associated protein 1; MAPK: (mitogen-activated protein kinase; TGF-β: transforming growth factor-β; VCAM1: vascular cell adhesion molecule 1; PDGFA: platelet derived growth factor A; PDGFB: platelet derived growth factor B; PD-L1: programmed cell death 1 ligand 1.