Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer
Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer
复制标题
肿瘤相关巨噬细胞衍生的 CXCL8 通过在胃癌中自主表达 PD-L1 来决定免疫逃避。
DOI：
10.1136/gutjnl-2018-316324
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发表时间：
2019-10-01
期刊：
影响因子：
24.5
通讯作者：
Xu, Jiejie
中科院分区：
文献类型：
--
作者：
Lin, Chao;He, Hongyong;Xu, Jiejie
目的：我们先前的研究已确定CXCL8是导致因RACK1缺失介导的胃癌转移的关键趋化因子。然而，CXCL8对胃癌免疫监视的调节作用仍不清楚。
设计：采用流式细胞术分析检测76例胃癌患者新鲜肿瘤组织中CXCL8的主要来源以及免疫细胞的表型。通过实时定量PCR分析胃癌组织中CXCL8的mRNA水平。对于免疫组化分析，共纳入420例接受根治性切除的胃癌患者。对新鲜肿瘤组织进行体外培养以评估阻断胃癌中CXCL8通路的潜在治疗效果。
结果：CXCL8水平升高预示胃癌患者临床预后不良和肿瘤进展。在胃癌组织中，CXCL8主要由巨噬细胞分泌，集落刺激因子2（CSF - 2）促进巨噬细胞来源的CXCL8分泌。高水平的CXCL8与CD8(+) T细胞浸润减少以及Ki67(+) CD8(+) T细胞比例降低相关。此外，CXCL8还通过诱导巨噬细胞上PD - L1的表达抑制CD8(+) T细胞功能。最后，我们发现一种小分子CXCR2抑制剂瑞帕利辛可减少程序性死亡配体1（PD - L1(+)）巨噬细胞并促进抗肿瘤免疫。因此，高水平的CXCL8(+)巨噬细胞与胃癌患者不良预后呈正相关。
结论：CXCL8主要由巨噬细胞分泌，并通过诱导胃癌中的PD - L1(+)巨噬细胞促进免疫抑制微环境的形成。CXCL8抑制剂可能驱动抗肿瘤反应，为胃癌患者提供潜在的治疗效果。
Objective Our previous studies have identified CXCL8 as the crucial chemokine responsible for gastric cancer metastasis mediated by loss of RACK1. However, the regulatory effect of CXCL8 on immune surveillance in gastric cancer remains obscure. Design Flow cytometry analyses were performed to examine major source of CXCL8 and phenotypes of immune cells in fresh tumour tissues from 76 patients with gastric cancer. Real-time PCR was performed to analyse CXCL8 mRNA level in gastric cancer tissues. For immunohistochemical analyses, a total of 420 patients with gastric cancer undergoing curative resection were enrolled. In vitro culture of fresh tumour tissue was performed to evaluate the potential therapeutic effect of blocking CXCL8 pathway in gastric cancer. Results Increased level of CXCL8 indicates poor clinical outcome and tumour progression in patients with gastric cancer. In gastric cancer tissues, CXCL8 is predominantly secreted by macrophages and colony stimulating factor 2 (CSF-2) facilitates macrophage-derived CXCL8 secretion. High level of CXCL8 is associated with decreased CD8+ T cells infiltration and Ki67+ CD8+ T cells proportion. Moreover, CXCL8 also inhibits CD8+ T cells function by inducing the expression of PD-L1 on macrophages. Finally, we show that a small-molecule CXCR2 inhibitor, reparixin, drives the decreased programmed death-ligand 1 (PD-L1+) macrophages and promotes antitumour immunity. Accordingly, high levels of CXCL8+ macrophages are positively correlated with poor prognosis in patients with gastric cancer. Conclusions CXCL8 is predominantly secreted by macrophages and contributes to the immunosuppressive microenvironment by inducing PD-L1+ macrophages in gastric cancer. CXCL8 inhibitors may drive antitumour response, providing potential therapeutic effects for patients with gastric cancer.