Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway.,Cell Death and Differentiation

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Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-12-04 , DOI: 10.1038/s41418-019-0460-0
Chao Liu _{1,

2} , Zhaoying Yao _{1,

2} , Jianing Wang ₃ , Wen Zhang _{1,

2} , Yan Yang ₄ , Yan Zhang ₅ , Xinliang Qu ₆ , Yubing Zhu _{1,

2} , Jianjun Zou _{1,

2} , Sishi Peng _{2,

7} , Yan Zhao _{1,

2} , Shuli Zhao ₇ , Bangshun He ₇ , Qiongyu Mi ₇ , Xiuting Liu ₈ , Xu Zhang _{9,

10,

11} , Qianming Du ₇

Affiliation

Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
Neurobiology Laboratory, Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing, 210009, PR China.
Department of Pharmacy, The Third People's Hospital of Chengdu & Affiliated Hospital of Southwest Jiaotong University, 82 Qing Long Street, Chengdu, 610031, PR China.
Department of Gastroenterology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Department of Pharmacy, The First People's Hospital of Chengdu & Affiliated Hospital of Chengdu Medical College, 18 Wanxiang East Road, Chengdu, 610041, PR China.
Affiliated Hospital of integrated traditional Chinese and Western Medicine of Chengdu Medical College, 783 Xindu Avenue, Chengdu, 610031, PR China.
Affiliated Hospital of integrated traditional Chinese and Western Medicine of Chengdu University of TCM, 37, Twelve Bridges Road, Chengdu, 610031, PR China.

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.

中文翻译：

巨噬细胞衍生的 CCL5 通过 p65/STAT3-CSN5-PD-L1 通路促进结直肠癌细胞的免疫逃逸。

浸润的巨噬细胞是肿瘤微环境的重要组成部分，通过促进免疫逃避而在肿瘤的发生和发展中发挥作用。然而，巨噬细胞衍生细胞因子促进结直肠癌 (CRC) 免疫逃逸的分子机制尚不清楚。在这里，我们证明了由脂多糖 (LPS) 或高胆固醇饮食 (HCD) 诱导的巨噬细胞浸润显着促进了 CRC 的生长。同样，LPS 和 poly (I:C) 显着增加了 CT26 细胞同种异体移植肿瘤的体积。由巨噬细胞分泌的 CC 基序趋化因子配体 5 (CCL5) 通过在体外和体内稳定 PD-L1 抑制 T 细胞介导的 HT29 细胞杀伤并促进免疫逃逸。从机制上讲，CCL5 导致核因子 kappa-B p65/STAT3 复合物的形成，它与 COP9 信号体 5 (CSN5) 启动子结合，导致其上调。此外，CSN5 调节了 PD-L1 的去泛素化和稳定性。CSN5 在 CRC 中的高表达与显着缩短的生存期相关。此外，化合物 15 被鉴定为 CSN5 的抑制剂，并使 PD-L1 不稳定以减轻肿瘤负担。我们的研究结果表明，新的 CCL5-p65/STAT3-CSN5-PD-L1 信号轴在 CRC 动物模型中被 LPS 或 HCD 驱动的巨噬细胞浸润显着激活，这可能对人类癌症具有治疗和预后意义。化合物 15 被确定为 CSN5 的抑制剂，并破坏 PD-L1 以减轻肿瘤负担。我们的研究结果表明，新的 CCL5-p65/STAT3-CSN5-PD-L1 信号轴在 CRC 动物模型中被 LPS 或 HCD 驱动的巨噬细胞浸润显着激活，这可能对人类癌症具有治疗和预后意义。化合物 15 被确定为 CSN5 的抑制剂，并破坏 PD-L1 以减轻肿瘤负担。我们的研究结果表明，新的 CCL5-p65/STAT3-CSN5-PD-L1 信号轴在 CRC 动物模型中被 LPS 或 HCD 驱动的巨噬细胞浸润显着激活，这可能对人类癌症具有治疗和预后意义。

更新日期：2019-12-04

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