State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
Tianjin Key Laboratory of Early Druggability Evaluation of Innovative Drugs, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
J Nanobiotechnology. 2023 Jul 5;21(1):208. doi: 10.1186/s12951-023-01967-3.
The immune checkpoint inhibitor (ICI) anti-PD-L1 monoclonal antibody can inhibit the progress of hepatocellular carcinoma (HCC). Epithelial-mesenchymal transformation (EMT) can promote tumor migration and the formation of immune-suppression microenvironment, which affects the therapeutic effect of ICI. Yin-yang-1 (YY1) is an important transcription factor regulating proliferation, migration and EMT of tumor cells. This work proposed a drug-development strategy that combined the regulation of YY1-mediated tumor progression with ICIs for the treatment of HCC.
We first studied the proteins that regulated YY1 expression by using pull-down, co-immunoprecipitation, and duo-link assay. The active compound regulating YY1 content was screened by virtual screening and cell-function assay. Isorhamnetin (ISO) and anti-PD-L1 antibody dual-functional mesoporous silica nanoparticles (HMSN-ISO@ProA-PD-L1 Ab) were prepared as an antitumor drug to play a synergistic anti-tumor role.
YY1 can specifically bind with the deubiquitination enzyme USP7. USP7 can prevent YY1 from ubiquitin-dependent degradation and stabilize YY1 expression, which can promote the proliferation, migration and EMT of HCC cells. Isorhamnetin (ISO) were screened out, which can target USP7 and promote YY1 ubiquitin-dependent degradation. The cell experiments revealed that the HMSN-ISO@ProA-PD-L1 Ab nanoparticles can specifically target tumor cells and play a role in the controlled release of ISO. HMSN-ISO@ProA-PD-L1 Ab nanoparticles inhibited the growth of Hepa1-6 transplanted tumors and the effect was better than that of PD-L1 Ab treatment group and ISO treatment group. HMSN-ISO@ProA-PD-L1 Ab nanoparticles also exerted a promising effect on reducing MDSC content in the tumor microenvironment and promoting T-cell infiltration in tumors.
The isorhamnetin and anti-PD-L1 antibody dual-functional nanoparticles can improve tumor immune microenvironment and inhibit YY1-mediated tumor progression. This study demonstrated the possibility of HCC treatment strategies based on inhibiting USP7-mediated YY1 deubiquitination combined with anti-PD-L1 monoclonal Ab.
免疫检查点抑制剂（ICI）抗 PD-L1 单克隆抗体可抑制肝细胞癌（HCC）的进展。上皮-间充质转化（EMT）可促进肿瘤迁移和免疫抑制微环境的形成，影响 ICI 的治疗效果。阴阳-1（YY1）是一种重要的转录因子，可调节肿瘤细胞的增殖、迁移和 EMT。本工作提出了一种将 YY1 介导的肿瘤进展与 ICIs 联合用于 HCC 治疗的药物开发策略。
我们首先通过下拉、免疫共沉淀和 duo-link 测定研究了调节 YY1 表达的蛋白质。通过虚拟筛选和细胞功能测定筛选出调节 YY1 含量的活性化合物。异鼠李素（ISO）和抗 PD-L1 抗体双功能介孔硅纳米粒子（HMSN-ISO@ProA-PD-L1 Ab）被制备成抗肿瘤药物，以发挥协同抗肿瘤作用。
YY1 可特异性结合去泛素化酶 USP7。USP7 可防止 YY1 发生泛素依赖性降解并稳定 YY1 表达，从而促进 HCC 细胞的增殖、迁移和 EMT。筛选出异鼠李素（ISO），其可靶向 USP7 并促进 YY1 泛素依赖性降解。细胞实验表明，HMSN-ISO@ProA-PD-L1 Ab 纳米粒子可特异性靶向肿瘤细胞，并发挥 ISO 的控制释放作用。HMSN-ISO@ProA-PD-L1 Ab 纳米粒子抑制 Hepa1-6 移植瘤的生长，效果优于 PD-L1 Ab 治疗组和 ISO 治疗组。HMSN-ISO@ProA-PD-L1 Ab 纳米粒子还在减少肿瘤微环境中 MDSC 含量和促进肿瘤中 T 细胞浸润方面发挥了良好的作用。
异鼠李素和抗 PD-L1 抗体双功能纳米粒子可改善肿瘤免疫微环境并抑制 YY1 介导的肿瘤进展。本研究证明了基于抑制 USP7 介导的 YY1 去泛素化与抗 PD-L1 单克隆 Ab 联合治疗 HCC 的策略的可能性。
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