免疫疗法
癌症研究
肝细胞癌
Wnt信号通路
免疫检查点
体内
肽
CD8型
化学
免疫系统
医学
药理学
信号转导
免疫学
生物
生物化学
生物技术
作者
Zheng‐Jun Zhou,Xiao Li,Guang Yang,Jingmei Wang,Baohua Li,Yinong Huang,Yan Jin,Kaishan Tao
出处
期刊:Theranostics
[Ivyspring International Publisher]
日期:2023-01-01
卷期号:13 (10): 3371-3386
被引量:8
摘要
Objective:The low clinical utility of immune checkpoint inhibitors (ICIs) against PD-1 or PD-L1 has recently been associated with the activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma (HCC), which promotes tumor immune escape and resistance to anti-PD-1/PD-L1 therapy.Hence, we aimed to fabricate a supramolecular peptide which could target the Wnt/β-catenin signaling pathway coupled with ICIs blockage therapy for optimizing HCC immunotherapy.Methods: A racemic spherical supramolecular peptide termed sBBI&PDP nanoparticle was constructed by hierarchical self-assembly, comprising an L-enantiomeric peptide as an inhibitor of BCL9 and β-catenin (sBBI) and a D-enantiomeric peptide as an inhibitor of PD-1/PD-L1 (PDP).Results: sBBI&PDP nanoparticle potently suppressed the hyperactivated Wnt/β-catenin signaling pathway in vitro and in vivo, while blocking endogenous PD-L1 effectively.Furthermore, sBBI&PDP increased the infiltration and action of CD8 + T cells at tumor sites.Notably, compared with the original sBBI and commercial Anti-PD-L1 inhibitors, the designed sBBI&PDP showed stronger antitumor efficacy in an orthotopic homograft mice model of HCC and a PDX HCC model in Hu-PBMC-NSG mice.Moreover, sBBI&PDP possessed a favorable biosafety profile. Conclusion:The successful implementation of this strategy could revitalize ICIs blockage therapy and promote the discovery of artificial peptides for HCC immunotherapy.
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