Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment
Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment
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新型小分子 PD-L1 抑制剂诱导 PD-L1 内化并优化免疫微环境。
DOI：
10.1021/acs.jmedchem.2c01801
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发表时间：
2022-12-29
影响因子：
7.3
通讯作者：
Yang, Peng
中科院分区：
文献类型：
--
作者：
Sun, Chengliang;Yin, Mingxiao;Yang, Peng
阻断PD-1/PD-L1相互作用已成为肿瘤治疗的重要策略，在临床上显示出突出的治疗效果。然而，不令人满意的应答率和免疫相关的不良反应限制了抗PD 1/PD-L1抗体的使用。在这里，我们报告了S4-1的发现和鉴定，这是一种创新的PD-L1小分子抑制剂。在体外，S4-1有效地改变PD-L1/PD-1相互作用，诱导PD-L1二聚化和内化，改善其在内质网的定位，从而增强外周血单个核细胞对肿瘤细胞的细胞毒性。在体内，S4-1显著抑制肺癌和结直肠癌模型中的肿瘤生长，特别是结直肠癌，导致部分肿瘤细胞完全清除。此外，S4-1诱导T细胞活化并逆转抑制性肿瘤微环境，与PD-L1/PD-1通路阻断一致。这些数据支持继续评价S4-1作为替代ICB治疗策略。
Blocking the PD-1/PD-L1 interaction has become an important strategy for tumor therapy, which has shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse effects limit the use of anti-PD1/PD-L1 antibodies. Here, we report the discovery and identification of S4-1, an innovative small-molecule inhibitor of PD-L1. In vitro, S4-1 effectively altered the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, improved its localization to endoplasmic reticulum, and thus enhanced the cytotoxicity of peripheral blood mononuclear cells toward tumor cells. In vivo, S4-1 significantly inhibited tumor growth in both lung and colorectal cancer models, particularly in colorectal cancer, where it led to complete clearance of a portion of the tumor cells. Furthermore, S4-1 induced T-cell activation and inversed the inhibitory tumor microenvironment, consistent with the PD-L1/PD-1 pathway blockade. These data support the continued evaluation of S4-1 as an alternative ICB therapeutic strategy.