Discovery of low-molecular weight anti-PD-L1 peptides for cancer immunotherapy
Discovery of low-molecular weight anti-PD-L1 peptides for cancer immunotherapy
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DOI：
10.1186/s40425-019-0705-y
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发表时间：
2019-10-22
影响因子：
10.9
通讯作者：
Cheng, Kun
中科院分区：
文献类型：
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作者：
Liu, Hao;Zhao, Zhen;Cheng, Kun
背景资料：使用检查点抑制剂，特别是PD-1/PD-L1抑制剂的免疫疗法现已发展成为癌症患者最有希望的治疗方法。然而，这些抑制剂中的大多数是单克隆抗体，并且它们的大尺寸可能限制它们的肿瘤渗透，导致次优疗效。因此，人们越来越关注开发低分子量的checkpoint inhibitors.Methods：我们开发了一种新的生物淘选策略来发现基于小肽的抗PD-L1抑制剂。使用各种测定法检查肽对PD-L1的亲和力和特异性。进行三维（3D）球体渗透研究以确定肽的肿瘤渗透能力。结果：发现了几种能阻断PD-1/PD-L1相互作用的抗PD-L1多肽抑制剂。这些肽对人PD-L1蛋白以及PD-L1过表达人癌细胞MDA-MB-231和DU-145表现出高亲和力和特异性。分子对接研究表明，肽CLP 002在PD-L1与PD-1相互作用的残基处特异性结合PD-L1。该肽还阻断CD 80/PD-L1相互作用，这可能进一步增强肿瘤浸润性T细胞的免疫应答。与抗体相比，肽CLP 002在3D肿瘤球体模型中表现出更好的肿瘤穿透。肽CLP 002恢复与癌细胞共培养的T细胞的增殖并防止其凋亡。肽CLP 002也抑制肿瘤生长，并增加生存的CT 26荷瘤mice.Conclusions：这项研究表明，使用噬菌体展示发现小肽为基础的检查点抑制剂的可行性。我们的研究结果还表明，抗PD-L1肽是一种有前途的低分子量检查点抑制剂，可用于癌症免疫治疗。
Background: Immunotherapy using checkpointinhibitors, especially PD-1/PD-L1 inhibitors, has now evolved into the most promising therapy for cancer patients. However, most of these inhibitors are monoclonal antibodies, and their large size may limit their tumor penetration, leading to suboptimal efficacy. As a result, there has been a growing interest in developing low-molecular-weight checkpoint inhibitors.Methods: We developed a novel biopanning strategy to discover small peptide-based anti-PD-L1 inhibitors. The affinity and specificity of the peptides to PD-L1 were examined using various assays. Three-dimensional (3D) spheroid penetration study was performed to determine the tumor penetration capability of the peptides. Antitumor activity of the peptides was evaluated in mice bearing CT26 tumor cells.Results: We discover several anti PD-L1 peptide inhibitors to block PD-1/PD-L1 interaction. The peptides exhibit high affinity and specificity to human PD-L1 protein as well as PD-L1-overexpressing human cancer cells MDA-MB-231 and DU-145. Molecular docking studies indicate that the peptide CLP002 specifically binds to PD-L1 at the residues where PD-L1 interacts with PD-1. The peptide also blocks the CD80/PD-L1 interaction, which may further enhance the immune response of tumor-infiltrating T cells. Compared to antibody, the peptide CLP002 exhibits better tumor penetration in a 3D tumor spheroid model. The peptide CLP002 restores proliferation and prevents apoptosis of T cells that are co-cultured with cancer cells. The peptide CLP002 also inhibits tumor growth and increases survival of CT26 tumor-bearing mice.Conclusions: This study demonstrated the feasibility of using phage display to discover small peptide-based checkpoint inhibitors. Our results also suggested that the anti-PD-L1 peptide represents a promising low-molecular-weight checkpoint inhibitor for cancer immunotherapy.