Zhuo-Kun Chen, Shuo Zheng, Yan Long, Kui-Ming Wang, Bo-Lin Xiao, Jin-Bang Li, Wei Zhang, Heng Song, Gang Chen
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引用次数: 0
摘要
肿瘤衍生的小细胞外囊泡 (sEV) 上的程序性死亡配体 1 (PD-L1) 与宿主免疫细胞上的 PD-1 受体相互作用,从而限制了治疗效果。靶向分泌 sEV PD-L1 已成为增强免疫疗法的一种有前途的策略。然而,小分子抑制剂的缺乏给临床转化带来了挑战。在本研究中,我们开发了一种靶点和表型双驱动高通量筛选(TAP-HTS)策略,该策略将虚拟筛选与基于纳米流的实验验证相结合。我们发现布洛芬(IBP)是一种有效靶向 sEV PD-L1 分泌的新型抑制剂。IBP 通过与 sEV 生物发生的关键调控因子--肝细胞生长因子调控酪氨酸激酶底物(HRS)发生物理作用,破坏了肿瘤细胞中 PD-L1+ sEV 的生物发生和分泌。值得注意的是,IBP 的作用机制不同于其通常已知的靶点--环氧化酶(COX1 或 COX2)。在黑色素瘤和口腔鳞状细胞癌(OSCC)小鼠模型中,施用 IBP 可刺激抗肿瘤免疫,增强抗 PD-1 疗法的疗效。为了解决潜在的不良反应,我们进一步开发了一种用于局部应用的 IBP 凝胶,该凝胶与抗 PD-1 治疗联合使用时显示出显著的疗效。这种特异性小抑制剂的发现为建立持久的全身性抗肿瘤免疫提供了一条前景广阔的途径。
High-throughput screening identifies ibuprofen as a small extracellular vesicle PD-L1 inhibitor for synergistic cancer immunotherapy.
Programmed death-ligand 1 (PD-L1) on tumor-derived small extracellular vesicles (sEVs) limits therapeutic effectiveness by interacting with the PD-1 receptor on host immune cells. Targeting the secretion of sEV PD-L1 has emerged as a promising strategy to enhance immunotherapy. However, the lack of small-molecule inhibitors poses a challenge for clinical translation. In this study, we developed a target and phenotype dual-driven high-throughput screening (TAP-HTS) strategy that combined virtual screening with nanoflow-based experimental verification. We identified ibuprofen (IBP) as a novel inhibitor that effectively targeted sEV PD-L1 secretion. IBP disrupted the biogenesis and secretion of PD-L1+ sEVs in tumor cells by physically interacting with a critical regulator of sEV biogenesis, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS). Notably, the mechanism of action of IBP is distinct from its commonly known targets, cyclooxygenases (COX1 or COX2). Administration of IBP stimulated antitumor immunity and enhanced the efficacy of anti-PD-1 therapy in melanoma and oral squamous cell carcinoma (OSCC) mouse models. To address potential adverse effects, we further developed an IBP gel for topical application, which demonstrated remarkable therapeutic efficacy when combined with anti-PD-1 treatment. The discovery of this specific small inhibitor provides a promising avenue for establishing durable, systemic antitumor immunity.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.