Extracellular Vesicles From Gastric Cancer Cells Induce PD-L1 Expression on Neutrophils to Suppress T-Cell Immunity
Extracellular Vesicles From Gastric Cancer Cells Induce PD-L1 Expression on Neutrophils to Suppress T-Cell Immunity
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胃癌细胞的细胞外囊泡诱导中性粒细胞表达 PD-L1，从而抑制 T 细胞免疫
DOI：
10.3389/fonc.2020.00629
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发表时间：
2020-05-13
影响因子：
4.7
通讯作者：
Zhang, Xu
中科院分区：
文献类型：
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作者：
Shi, Yinghong;Zhang, Jiahui;Zhang, Xu
中性粒细胞是实体瘤的主要成分，在不同的肿瘤环境中表现出不同的表型。我们先前已经表明，肿瘤细胞外囊泡（EV）可以诱导嗜中性粒细胞的促肿瘤激活;然而，肿瘤EV诱导的嗜中性粒细胞在肿瘤免疫中的作用仍不清楚。在此，我们报道了胃癌细胞来源的EV（GC-EV）诱导中性粒细胞上程序性死亡配体1（PD-L1）的表达。GC-EV转运高迁移率族蛋白1（HMGB 1）以激活信号转导和转录激活因子3（STAT 3）并上调中性粒细胞中的PD-L1基因表达。阻断STAT 3通路和沉默HMGB 1逆转GC-EV诱导的中性粒细胞PD-L1表达。GC-EV诱导的中性粒细胞在体外抑制T细胞增殖、活化和功能，这可以被特异性PD-L1抗体拮抗。此外，GC组织衍生的EV也显示出类似的效果。总之，我们的结果表明，来自GC微环境的EV诱导中性粒细胞上的PD-L1表达以抑制T细胞免疫，这为中性粒细胞在GC中的促肿瘤作用提供了新的见解，并揭示了EV在协调免疫抑制微环境中的多方面作用。
Neutrophils are prominent components of solid tumors and exhibit distinct phenotypes in different tumor milieu. We have previously shown that tumor extracellular vesicles (EVs) could induce pro-tumor activation of neutrophils; however, the role of tumor EV-elicited neutrophils in tumor immunity remains unclear. Herein, we reported that gastric cancer cell-derived EVs (GC-EVs) induced the expression of programmed death-ligand 1 (PD-L1) on neutrophils. GC-EVs transported high-mobility group box-1 (HMGB1) to activate signal transducer and activator of transcription 3 (STAT3) and upregulate PD-L1 gene expression in neutrophils. Blocking STAT3 pathway and silencing HMGB1 reversed GC-EV-induced PD-L1 expression on neutrophils. GC-EV-elicited neutrophils suppressed T cell proliferation, activation, and function in vitro, which could be antagonized by a specific PD-L1 antibody. Furthermore, GC tissue-derived EVs also showed similar effects. Taken together, our results indicate that EVs from the GC microenvironment induce PD-L1 expression on neutrophils to suppress T-cell immunity, which provides a new insight into the pro-tumor roles of neutrophils in GC and sheds light on the multifaceted roles of EVs in orchestrating an immunosuppressive microenvironment.