| Literature DB >> 31802034 |
Chao Liu1,2, Zhaoying Yao1,2, Jianing Wang3, Wen Zhang1,2, Yan Yang4, Yan Zhang5, Xinliang Qu6, Yubing Zhu1,2, Jianjun Zou1,2, Sishi Peng2,7, Yan Zhao1,2, Shuli Zhao7, Bangshun He7, Qiongyu Mi7, Xiuting Liu8, Xu Zhang9,10,11, Qianming Du12.
Abstract
Infiltrated macrophages are an important constituent of the tumor microenvironment and play roles in tumor initiation and progression by promoting immune evasion. However, the molecular mechanism by which macrophage-derived cytokines foster immune escape of colorectal cancer (CRC) is unclear. Here, we demonstrated that macrophage infiltration induced by lipopolysaccharide (LPS) or a high-cholesterol diet (HCD) significantly promoted CRC growth. Similarly, LPS and poly (I:C) remarkably increased the volume of CT26 cell allograft tumors. C-C motif chemokine ligand 5 (CCL5), which is secreted by macrophages, inhibited T-cell-mediated killing of HT29 cells and promoted immune escape by stabilizing PD-L1 in vitro and in vivo. Mechanistically, CCL5 resulted in formation of nuclear factor kappa-B p65/STAT3 complexes, which bound to the COP9 signalosome 5 (CSN5) promoter, leading to its upregulation. Moreover, CSN5 modulated the deubiquitination and stability of PD-L1. High expression of CSN5 in CRC was associated with significantly shorter survival. Furthermore, compound-15 was identified as an inhibitor of CSN5, and destabilized PD-L1 to alleviate the tumor burden. Our results suggest that the novel CCL5-p65/STAT3-CSN5-PD-L1 signaling axis is significantly activated by LPS or HCD-driven macrophage infiltration in an animal model of CRC, which likely has therapeutic and prognostic implications for human cancers.Entities:
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Year: 2019 PMID： 31802034 PMCID： PMC7244707 DOI： 10.1038/s41418-019-0460-0
Source DB: PubMed Journal: Cell Death Differ ISSN： 1350-9047 Impact factor: 15.828