Qin Yingzhou, Meng Xiangzhou, Li Lin, Liu Cuijuan, Gao Fan, Yuan Xin, Huang Ying, Zhu Yimin
School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, 230026, China; CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China.
CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China.
Eur J Pharmacol. 2023 Dec 5;960:176144. doi: 10.1016/j.ejphar.2023.176144. Epub 2023 Oct 20.
Immune checkpoint inhibitors, particularly monoclonal antibodies blocking the programmed cell death 1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway, have been successfully utilized in the clinic. However, certain drawbacks associated with antibodies, such as high immunogenicity and poor tissue penetration, need to be addressed for their broader clinical application. Peptides, as low molecular weight alternatives, have garnered increasing interest in this field. In this study, we employed bacterial surface display technology to identify a PD-1-binding peptide, PBP. The PBP peptide exhibited moderate affinity for human PD-1 (hPD-1) and displayed cross-reactivity with mouse PD-1 (mPD-1). Molecular docking analysis revealed that the interaction residues of the PBP peptide with PD-1 played crucial roles in the formation of the PD-1/PD-L1 complex. A competing binding assay demonstrated that the peptide could interfere the interaction of PD-1 and PD-L1. Moreover, in vitro experiments showed that the PBP peptide could reinvigorate T cells inhibited by PD-L1. In an in vivo mouse model of CT26, the PBP peptide effectively suppressed tumor growth by enhancing T cell function. In conclusion, our results suggest that the PBP peptide exerts an anti-tumor effect by impeding the interplay between PD-1 and PD-L1, highlighting its potential as an alternative for tumor immunotherapy.
免疫检查点抑制剂,尤其是阻断程序性细胞死亡蛋白1(PD-1)/程序性细胞死亡配体1(PD-L1)通路的单克隆抗体,已在临床上成功应用。然而,与抗体相关的某些缺点,如高免疫原性和较差的组织穿透性,需要加以解决以实现其更广泛的临床应用。肽作为低分子量的替代物,在该领域已引起越来越多的关注。在本研究中,我们利用细菌表面展示技术鉴定出一种与PD-1结合的肽,即PBP。PBP肽对人PD-1(hPD-1)表现出中等亲和力,并与小鼠PD-1(mPD-1)具有交叉反应性。分子对接分析表明,PBP肽与PD-1的相互作用残基在PD-1/PD-L1复合物的形成中起关键作用。竞争性结合试验表明,该肽可干扰PD-1与PD-L1的相互作用。此外,体外实验表明,PBP肽可使受PD-L1抑制的T细胞恢复活力。在CT26小鼠体内模型中,PBP肽通过增强T细胞功能有效抑制肿瘤生长。总之,我们的结果表明,PBP肽通过阻碍PD-1与PD-L1之间的相互作用发挥抗肿瘤作用,突出了其作为肿瘤免疫治疗替代物的潜力。