Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway

Chao Liu, Zhaoying Yao, Jianing Wang, Wen Zhang, Yan Yang, Yan Zhang, Xinliang Qu, Yubing Zhu, Jianjun Zou, Sishi Peng, Yan Zhao, Shuli Zhao, Bangshun He, Qiongyu Mi, Xiuting Liu, Xu Zhang, Qianming Du

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

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.

Original languageEnglish
Pages (from-to)1765-1781
Number of pages17
JournalCell Death and Differentiation
Volume27
Issue number6
DOIs
StatePublished - Jun 1 2020

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