Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export
文献类型：期刊论文
| 作者 | Chen, Fang-Fang1,2,4; Li, Zheng3; Ma, Dawei3; Yu, Qiang1,2
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| 刊名 | ONCOIMMUNOLOGY
 |
| 出版日期 | 2020 |
| 卷号 | 9期号:1页码:11 |
| 关键词 | BMS1166 PD-L1 PD-1 glycosylation ER export |
| ISSN号 | 2162-402X |
| DOI | 10.1080/2162402X.2020.1831153 |
| 通讯作者 | Yu, Qiang(qyu@sibs.ac.cn) |
| 英文摘要 | Therapeutic monoclonal antibodies against the PD-L1/PD-1 (programmed death ligand-1/programmed cell death protein-1) axis have achieved great successes in cancer treatments, but the development of small-molecule immunomodulators of the pathway has lagged far behind. We established a cellular coculture assay with two stable transfectant cell lines, a PD-L1-expressing tumor cell line PC9/PD-L1 and a PD-1-expressing T cell line Jurkat/PD-1. Western blotting analyses were used to monitor the PD-L1/PD-1 interaction and signaling. We analyzed PD-L1 glycosylation by lectin binding assay and glycosidase digestion, and examined subcellular localization of PD-L1 by immunocytochemical staining. Luciferase assay and real-time PCR were used to evaluate T cell activation in the coculture experiments. We found that coculturing of the PC9/PD-L1 cells with the Jurkat/PD-1 cells induced a lysosomal degradation of PD-1. A small-molecule PD-L1 inhibitor BMS1166 developed by Bristol-Myers Squibb inhibited the coculture-induced PD-1 degradation through a unique mechanism. BMS1166 specifically affected PD-L1 glycosylation and prevented transporting of the under-glycosylated form of PD-L1 from endoplasmic reticulum (ER) to Golgi, leading to accumulation of PD-L1 in ER. In doing so, BMS1166 blocked PD-L1/PD-1 signaling. Coculturing PD-L1-expressing cells with PD-1-expressing cells induced degradation of PD-1, which could be used as a readout to identify inhibitors of PD-L1/PD-1 signaling. The small-molecule PD-L1 inhibitor BMS1166 abolished the glycosylation and maturation of PD-L1 by blocking its exporting from ER to Golgi. Our study discovered a new strategy to identify inhibitors of the PD-L1/PD-1 signaling pathway and to develop new drugs for the treatment of cancer. |
| WOS关键词 | CANCER-CELLS ; IN-VITRO ; GLYCOSYLATION ; DEGRADATION ; MECHANISMS ; EXPRESSION ; PROTEIN |
| 资助项目 | National Natural Science Foundation of China[81673465] ; China National Key Research Program[2018YFC1705500] ; Natural Science Foundation of Shanghai[17ZR1437100] |
| WOS研究方向 | Oncology ; Immunology |
| 语种 | 英语 |
| WOS记录号 | WOS:000584581800001 |
| 出版者 | TAYLOR & FRANCIS INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/292538]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Yu, Qiang |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem,Ctr Excell, Shanghai, Peoples R China 4.Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Fang-Fang,Li, Zheng,Ma, Dawei,et al. Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export[J]. ONCOIMMUNOLOGY,2020,9(1):11. |
| APA | Chen, Fang-Fang,Li, Zheng,Ma, Dawei,&Yu, Qiang.(2020).Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export.ONCOIMMUNOLOGY,9(1),11. |
| MLA | Chen, Fang-Fang,et al."Small-molecule PD-L1 inhibitor BMS1166 abrogates the function of PD-L1 by blocking its ER export".ONCOIMMUNOLOGY 9.1(2020):11. |
入库方式： OAI收割
来源：上海药物研究所
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