Niclosamide improves cancer immunotherapy by modulating RNA-binding protein HuR-mediated PD-L1 signaling.
Niclosamide improves cancer immunotherapy by modulating RNA-binding protein HuR-mediated PD-L1 signaling.
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奈洛沙胺通过调节rna结合蛋白hur介导的PD-L1信号传导改善癌症免疫治疗。
DOI：
10.1186/s13578-023-01137-w
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发表时间：
2023-10-17
影响因子：
7.5
通讯作者：
Xu, Liang
中科院分区：
文献类型：
--
作者：
Zhang, Qi;Yang, Zhe;Hao, Xinbao;Dandreo, Lauren J.;He, Lily;Zhang, Yuxia;Wang, Fen;Wu, Xiaoqing;Xu, Liang
免疫检查点阻断（ICB）代表了癌症治疗的革命性进展，但在三阴性乳腺癌（TNBC）中的成功仍然有限。本研究旨在探讨RNA结合蛋白（RBP）HuR通过转录后调节PD-L1参与肿瘤免疫逃避的机制，并评估HuR抑制改善免疫应答的潜力。通过核糖核蛋白免疫沉淀和RNA下拉试验测定HuR与PD-L1 mRNA之间的结合。通过CRISPR/Cas9技术建立HuR敲除克隆。蛋白质水平通过Western印迹、免疫组织化学和免疫细胞化学进行评估。通过体外T细胞活化和杀伤试验及体内药效试验，探讨HuR-PD-L1的功能及分子机制。我们发现HuR直接结合并稳定PD-L1 mRNA。敲除HuR降低了PD-L1水平并促进了T细胞活化。我们发现氯硝柳胺通过抑制HuR细胞质易位减少PD-L1，并减少PD-L1的糖基化。氯硝柳胺增强了T细胞介导的对癌细胞的杀伤，并显著提高了抗PD-1免疫治疗在两种同基因动物肿瘤模型中的疗效。我们确定HuR是PD-L1的一种新的转录后调节因子，在肿瘤免疫逃避中起重要作用。氯硝柳胺可能是一种很有前途的再利用药物，通过靶向HuR-PD-L1轴来改善患者对免疫治疗的反应。我们的研究证明了一种靶向HuR/PD-L1的新策略，并为将氯硝柳胺重新用作HuR抑制剂以克服癌症免疫逃避并改善对ICB免疫治疗的反应提供了第一个原理证明。在线版本包含补充材料，可通过10.1186/s13578-023-01137-w获得。
Immune checkpoint blockade (ICB) represents a revolutionary advance in cancer treatment but remains limited success in triple-negative breast cancer (TNBC). Here we aim to explore the mechanism of RNA-binding protein (RBP) HuR in cancer immune evasion by post-transcriptionally regulating PD-L1 and evaluate the potential of HuR inhibition to improve immune response. The binding between HuR and PD-L1 mRNA was determined by ribonucleoprotein immunoprecipitation and RNA pull-down assays. The HuR knockout clones were established by CRISPR/Cas9 technology. The protein levels were assessed by Western blot, immunohistochemistry, and immunocytochemistry. The function and molecular mechanism of HuR-PD-L1 were determined by in vitro T cell activation and killing assay and in vivo efficacy assay. We found that HuR directly bound to and stabilized PD-L1 mRNA. Knocking out HuR reduced PD-L1 levels and promoted T cell activation. We discovered that niclosamide reduced PD-L1 by inhibiting HuR cytoplasmic translocation, and diminished glycosylation of PD-L1. Niclosamide enhanced T cell-mediated killing of cancer cells and significantly improved the efficacy of anti-PD-1 immunotherapy in two syngeneic animal tumor models. We identified HuR as a novel posttranscriptional regulator of PD-L1, which plays an important role in tumor immune evasion. Niclosamide might be a promising repurposed drug to improve the patient response to immunotherapy by targeting HuR-PD-L1 axis. Our study demonstrates a novel strategy for targeting HuR/PD-L1 and provides the first proof-of-principle for repurposing niclosamide as a HuR inhibitor to overcome cancer immune evasion and improve response to ICB immunotherapy. The online version contains supplementary material available at 10.1186/s13578-023-01137-w.
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影响因子：
4.7
作者：
通讯作者：
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影响因子：
14.2
作者：
Casolaro, Vincenzo;Fang, Xi;Stellato, Cristiana
通讯作者：
Stellato, Cristiana
影响因子：
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作者：
Calaluce R;Gubin MM;Davis JW;Magee JD;Chen J;Kuwano Y;Gorospe M;Atasoy U
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Atasoy U
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29.4
作者：
Li L;Hao X;Qin J;Tang W;He F;Smith A;Zhang M;Simeone DM;Qiao XT;Chen ZN;Lawrence TS;Xu L
通讯作者：
Xu L
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11.2
作者：
Guo, Xun;Hartley, Rebecca S.
通讯作者：
Hartley, Rebecca S.