TY - JOUR
T1 - Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway
AU - Liu, Chao
AU - Yao, Zhaoying
AU - Wang, Jianing
AU - Zhang, Wen
AU - Yang, Yan
AU - Zhang, Yan
AU - Qu, Xinliang
AU - Zhu, Yubing
AU - Zou, Jianjun
AU - Peng, Sishi
AU - Zhao, Yan
AU - Zhao, Shuli
AU - He, Bangshun
AU - Mi, Qiongyu
AU - Liu, Xiuting
AU - Zhang, Xu
AU - Du, Qianming
N1 - Funding Information:
Acknowledgements This work was supported by the National Natural Science Foundation of China (Nos. 81702833, 81703781, 81803513, and 81803763), the Natural Science Foundation of Jiangsu Province (Nos. BK20170137 and BK20170140), Sichuan Science and Technology Program (No. 2018JY0204), Natural Science Foundation of Chengdu Medical College (No. CYZ17-13), Innovation of medical research youth in Sichuan (Grant No. Q17012), Jiangsu Provincial Special Program of Medical Science (BE2019617) and the Science and Technology Development Fund Project of Nanjing Medical University (No. 2016NJMUZD041, 2016NJMUZD043, and NMUB2018315). We thank the Cellular and Molecular Biology Center of China Pharmaceutical University for assistance with confocal microscopy work and we are grateful to Xiao-Nan Ma for her technical help.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075911820&partnerID=8YFLogxK
U2 - 10.1038/s41418-019-0460-0
DO - 10.1038/s41418-019-0460-0
M3 - Article
C2 - 31802034
AN - SCOPUS:85075911820
SN - 1350-9047
VL - 27
SP - 1765
EP - 1781
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 6
ER -