Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer
Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer
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DOI：
10.1172/jci124037
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发表时间：
2020-07-01
影响因子：
15.9
通讯作者：
Savai, Rajkumar
中科院分区：
文献类型：
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作者：
Salazar, Ylia;Zheng, Xiang;Savai, Rajkumar
免疫微环境在肺癌控制与进展和转移中起关键作用。在这项研究中，我们探讨了肿瘤浸润淋巴细胞亚群对肺癌生物学的影响，通过研究在体外共培养，在体内小鼠模型，和人肺癌组织。淋巴细胞条件培养液（CM）诱导原代人肺癌细胞和细胞系的上皮-间质转化（EMT）和迁移。相应地，在人肺癌组织中检测到Th 9和Th 17细胞的主要积累，并且与较差的存活相关。将肺癌细胞与Th 9/Th 17细胞共培养或将它们暴露于相应的CM诱导癌细胞中的EMT，并调节与EMT和转移有关的基因的表达谱。这些特征由信号细胞因子IL-9和IL-17再现，这些细胞因子引起的基因调控谱部分重叠和部分互补。在WT、Rag 1（-/-）、II 9 r（-/-）和II 17 ra（-/-）小鼠中共注射Th 9/Th 17细胞与肿瘤细胞改变了肿瘤生长和转移。因此，通过中和抗体抑制IL-9或IL-17细胞因子降低EMT并减缓肺癌进展和转移。总之，Th 9和Th 17淋巴细胞诱导肺癌细胞EMT，从而促进迁移和转移扩散，并提供潜在的新的治疗策略。
Immune microenvironment plays a critical role in lung cancer control versus progression and metastasis. In this investigation, we explored the effect of tumor-infiltrating lymphocyte subpopulations on lung cancer biology by studying in vitro cocultures, in vivo mouse models, and human lung cancer tissue. Lymphocyte conditioned media (CM) induced epithelial-mesenchymal transition (EMT) and migration in both primary human lung cancer cells and cell lines. Correspondingly, major accumulation of Th9 and Th17cells was detected in human lung cancer tissue and correlated with poor survival. Coculturing lung cancer cells with Th9/Th17 cells or exposing them to the respective CM induced EMT in cancer cells and modulated the expression profile of genes implicated in EMT and metastasis. These features were reproduced by the signatory cytokines IL-9 and IL-17, with gene regulatory profiles evoked by these cytokines partly overlapping and partly complementary. Coinjection of Th9/Th17 cells with tumor cells in WT, Rag1(-/-), II9r(-/-), and II17ra(-/-) mice altered tumor growth and metastasis. Accordingly, inhibition of IL-9 or IL-17 cytokines by neutralizing antibodies decreased EMT and slowed lung cancer progression and metastasis. In conclusion, Th9 and Th17 lymphocytes induce lung cancer cell EMT, thereby promoting migration and metastatic spreading and offering potentially novel therapeutic strategies.