IL-17A secreted from lymphatic endothelial cells promotes tumorigenesis by upregulation of PD-L1 in hepatoma stem cells
IL-17A secreted from lymphatic endothelial cells promotes tumorigenesis by upregulation of PD-L1 in hepatoma stem cells
复制标题
淋巴内皮细胞分泌的IL-17A通过上调肝癌干细胞中的PD-L1促进肿瘤发生
DOI：
10.1016/j.jhep.2019.08.034
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发表时间：
2019-12-01
影响因子：
25.7
通讯作者：
Jiang, Jianhai
中科院分区：
文献类型：
--
作者：
Wei, Yuanyan;Shi, Danfang;Jiang, Jianhai
背景与目的：微环境调节肝癌干细胞的行为。然而，淋巴管内皮细胞对肝癌干细胞生态位的贡献仍然是未知的，我们的目的是分析这种贡献并阐明其背后的机制。方法：淋巴管内皮细胞与CD 133（+）肝癌干细胞之间的联系通过免疫荧光和粘附实验进行分析;用蛋白质印迹、定量逆转录PCR和荧光素酶报告基因分析检测它们的缔合对IL-17 A表达的影响。使用球体和肿瘤形成测定来检查IL-17 A对肝癌干细胞的自我更新和肿瘤发生的影响。采用流式细胞术检测IL-17 A在肝癌干细胞免疫逃逸中的作用。结果：CD 133（+）肝癌干细胞优先与淋巴管内皮细胞相互作用，CD 133（+）肝癌干细胞与淋巴管内皮细胞相互作用的程度不同。甘露糖受体与高甘露糖型N-聚糖之间的相互作用介导了CD 133（+）肝癌干细胞与淋巴管内皮细胞之间的相互作用。这种相互作用激活淋巴管内皮细胞中细胞因子IL 17 A的表达。IL-17 A促进肝癌干细胞的自我更新结论：淋巴管内皮细胞与肝癌干细胞之间的相互作用通过激活IL-17 A信号通路促进肝癌干细胞的自我更新和免疫逃逸。因此，抑制IL-17 A信号通路可能是一种有前途的肝癌治疗方法。Lay summary：微环境对肝癌干细胞的自我更新和发育至关重要，从而导致肝癌的发展。淋巴管内皮细胞是这种微环境的重要组成部分，通过上调IL-17 A信号传导，帮助肝癌干细胞自我更新和逃避免疫攻击。因此，靶向IL-17 A信号传导是治疗肝癌的潜在策略。(C)2019年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: The microenvironment regulates hepatoma stem cell behavior. However, the contributions of lymphatic endothelial cells to the hepatoma stem cell niche remain largely unknown; we aimed to analyze this contribution and elucidate the mechanisms behind it.Methods: Associations between lymphatic endothelial cells and CD133(+) hepatoma stem cells were analyzed by immunofluorescence and adhesion assays; with the effects of their association on IL-17A expression examined using western blot, quantitative reverse transcription PCR and luciferase reporter assay. The effects of IL-17A on the self-renewal and tumorigenesis of hepatoma stem cells were examined using sphere and tumor formation assays. The role of IL-17A in immune escape by hepatoma stem cells was examined using flow cytometry. The expression of IL-17A in hepatoma tissues was examined using immunohistochemistry.Results: CD133(+) hepatoma stem cells preferentially interact with lymphatic endothelial cells. The interaction between the mannose receptor and high-mannose type N-glycans mediates the interaction between CD133(+) hepatoma stem cells and lymphatic endothelial cells. This interaction activates cytokine IL17A expression in lymphatic endothelial cells. IL-17A promotes the self-renewal of hepatoma stem cells. It also promotes their immune escape, partly through upregulation of PD-Ll.Conclusion: Interactions between lymphatic endothelial cells and hepatoma stem cells promote the self-renewal and immune escape of hepatoma stem cells, by activating IL-17A signaling. Thus, inhibiting IL-17A signaling may be a promising approach for hepatoma treatment.Lay summary: The microenvironment is crucial for the self-renewal and development of hepatoma stem cells, which lead to the development of liver cancer. Lymphatic endothelial cells are an important component of this niche microenvironment, helping hepatoma stem cells to self-renew and escape immune attack, by upregulating IL-17A signaling. Thus, targeting IL-17A signaling is a potential strategy for the treatment of hepatoma. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.