Niclosamide improves cancer immunotherapy by modulating RNA-binding protein HuR-mediated PD-L1 signaling

Cell & Bioscience

Research

Zhe Yang¹  Xinbao Hao¹  Qi Zhang¹  Lauren J. Dandreo¹  Liang Xu²  Xiaoqing Wu³  Yuxia Zhang⁴  Lily He⁴  Fen Wang⁵ 

[1] Department of Molecular Biosciences, The University of Kansas, 1567 Irving Hill Rd, 66045-7534, Lawrence, KS, USA;Department of Molecular Biosciences, The University of Kansas, 1567 Irving Hill Rd, 66045-7534, Lawrence, KS, USA;Department of Radiation Oncology, The University of Kansas Medical Center, 66160, Kansas City, KS, USA;The University of Kansas Cancer Center, The University of Kansas Medical Center, 66160, Kansas City, KS, USA;Department of Molecular Biosciences, The University of Kansas, 1567 Irving Hill Rd, 66045-7534, Lawrence, KS, USA;The University of Kansas Cancer Center, The University of Kansas Medical Center, 66160, Kansas City, KS, USA;Department of Pharmacology, Toxicology & Therapeutics, The University of Kansas Medical Center, 66160, Kansas City, KS, USA;Department of Radiation Oncology, The University of Kansas Medical Center, 66160, Kansas City, KS, USA;

关键词: RNA-binding protein;    HuR;    PD-L1;    Immunotherapy;    Niclosamide;    Immune evasion;   

DOI  :  10.1186/s13578-023-01137-w

 received in 2023-03-02, accepted in 2023-09-21,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundImmune 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.MethodsThe 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.ResultsWe 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.ConclusionWe 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.

【 授权许可】

CC BY   
© Society of Chinese Bioscientists in America (SCBA) 2023

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