Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway
Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway
复制标题
巨噬细胞衍生的 CCL5 通过 p65/STAT3-CSN5-PD-L1 途径促进结直肠癌细胞的免疫逃逸
DOI：
10.1038/s41418-019-0460-0
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发表时间：
2020-06-01
影响因子：
12.4
通讯作者：
Du, Qianming
中科院分区：
文献类型：
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作者：
Liu, Chao;Yao, Zhaoying;Du, Qianming
浸润性巨噬细胞是肿瘤微环境的重要组成部分，通过促进免疫逃逸在肿瘤的发生和发展中发挥作用。然而，巨噬细胞来源的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，我们证明了脂多糖（LPS）或高胆固醇饮食（HCD）诱导的巨噬细胞浸润可显著促进结直肠癌的生长。同样，LPS和poly （I:C）显著增加了CT26细胞同种异体移植肿瘤的体积。巨噬细胞分泌的C-C基序趋化因子配体5 （C-C motif chemokine ligand 5, CCL5）在体外和体内通过稳定PD-L1抑制t细胞介导的HT29细胞杀伤，促进免疫逃逸。机制上，CCL5导致核因子kappa-B p65/STAT3复合物的形成，该复合物结合到COP9信号体5 （CSN5）启动子上，导致其上调。此外，CSN5调节PD-L1的去泛素化和稳定性。CSN5在结直肠癌中的高表达与较短的生存期相关。此外，化合物-15被鉴定为CSN5的抑制剂，并破坏PD-L1的稳定以减轻肿瘤负担。我们的研究结果表明，在CRC动物模型中，新的CCL5-p65/STAT3-CSN5-PD-L1信号轴被LPS或hcd驱动的巨噬细胞浸润显著激活，这可能对人类癌症具有治疗和预后意义。
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.