癌症研究
肿瘤微环境
免疫疗法
免疫系统
封锁
PD-L1
免疫检查点
外周血单个核细胞
癌症免疫疗法
T细胞
抗体
体内
化学
免疫学
体外
医学
生物
受体
生物化学
生物技术
作者
Chia‐Yi Lin,Kuo‐Yen Huang,Shih-Han Kao,Ming-Shiu Lin,Chang‐Yu Lin,Shuenn‐Chen Yang,Wei-Chia Chung,Ya‐Hsuan Chang,Rong‐Jie Chein,Pan‐Chyr Yang
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2023-04-07
卷期号:9 (14)
被引量:10
标识
DOI:10.1126/sciadv.ade9944
摘要
Immune checkpoint inhibitors (ICIs) targeting PD-L1 immunotherapy are state-of-the-art treatments for advanced non-small cell lung cancer (NSCLC). However, the treatment response of certain patients with NSCLC is unsatisfactory because of an unfavorable tumor microenvironment (TME) and poor permeability of antibody-based ICIs. In this study, we aimed to discover small-molecule drugs that can modulate the TME to enhance ICI treatment efficacy in NSCLC in vitro and in vivo. We identified a PD-L1 protein-modulating small molecule, PIK-93, using a cell-based global protein stability (GPS) screening system. PIK-93 mediated PD-L1 ubiquitination by enhancing the PD-L1-Cullin-4A interaction. PIK-93 reduced PD-L1 levels on M1 macrophages and enhanced M1 antitumor cytotoxicity. Combined PIK-93 and anti-PD-L1 antibody treatment enhanced T cell activation, inhibited tumor growth, and increased tumor-infiltrating lymphocyte (TIL) recruitment in syngeneic and human peripheral blood mononuclear cell (PBMC) line-derived xenograft mouse models. PIK-93 facilitates a treatment-favorable TME when combined with anti-PD-L1 antibodies, thereby enhancing PD-1/PD-L1 blockade cancer immunotherapy.
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