Enhancement of the antitumor effect of HER2-directed CAR-T cells through blocking epithelial-mesenchymal transition in tumor cells
Enhancement of the antitumor effect of HER2-directed CAR-T cells through blocking epithelial-mesenchymal transition in tumor cells
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通过阻断肿瘤细胞上皮间质转化增强HER2定向CAR-T细胞的抗肿瘤作用
DOI：
10.1096/fj.202000080rr
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Wang Wei
中科院分区：
文献类型：
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作者：
Zhang Peng-Fei;Huang Yong;Liang Xiao;Li Dan;Jiang Lin;Yang Xiao;Zhu Min;Gou Hong-Feng;Gong You-Ling;Wei Yu-Quan;Li Qiu;Wang Wei
嵌合抗原受体T （CAR - T）细胞治疗实体瘤的疗效远不能令人满意。在这项研究中，我们研究了上皮-间充质转化（epithelial - mesenchymal transition， EMT）对CAR - T细胞抗肿瘤作用的影响，并探讨了CAR - T细胞与靶向EMT的抑制剂联合使用的潜在疗效。我们成功地用TGF - β1诱导肿瘤细胞产生EMT，发现EMT显著抑制了HER2导向的CAR - T细胞的抗肿瘤作用。PD‐L1在EMT肿瘤细胞中表达上调，EMT过程中PD‐L1表达的变化依赖于MEK/ERK和PI3K/Akt通路。抑制TGF - β1通路可以阻断肿瘤细胞的EMT过程，恢复肿瘤细胞对HER2导向的CAR - T细胞的敏感性。此外，靶向TGF - β1通路在体内显著增强了HER2导向CAR - T细胞的抗肿瘤作用。我们的研究结果表明，阻断EMT可以有效地增强CAR - T细胞的抗肿瘤作用，这为提高CAR - T细胞治疗实体瘤的疗效提供了一条有希望的途径。
The efficacy of chimeric antigen receptor T (CAR‐T) cell therapy in solid tumors is far from satisfactory. In this study, we investigated the influence of epithelial‐mesenchymal transition (EMT) on the antitumor effect of CAR‐T cells and explored the potential efficacy of combining CAR‐T cells with inhibitors targeting EMT. We successfully induced EMT in tumor cells with TGF‐β1, and the antitumor effect of HER2‐directed CAR‐T cells was significantly suppressed by EMT. Upregulation of PD‐L1 was observed in tumor cells undergoing EMT, and change in PD‐L1 expression during the EMT process was dependent on the MEK/ERK and PI3K/Akt pathways. Inhibition of the TGF‐β1 pathway could block the EMT process in tumor cells and restore their susceptibility to HER2‐directed CAR‐T cells in vitro. In addition, targeting the TGF‐β1 pathway significantly enhanced the antitumor effect of HER2‐directed CAR‐T cells in vivo. Our findings suggest that blocking EMT could potently enhance the antitumor effect of CAR‐T cells, which provides a promising approach to improving the therapeutic efficacy of CAR‐T cell therapy in solid tumors.