1. IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion
- Author
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Chan, Li-Chuan, Li, Chia-Wei, Xia, Weiya, Hsu, Jung-Mao, Lee, Heng-Huan, Cha, Jong-Ho, Wang, Hung-Ling, Yang, Wen-Hao, Yen, Er-Yen, Chang, Wei-Chao, Zha, Zhengyu, Lim, Seung-Oe, Lai, Yun-Ju, Liu, Chunxiao, Liu, Jielin, Dong, Qiongzhu, Yang, Yi, Sun, Linlin, Wei, Yongkun, Nie, Lei, Hsu, Jennifer L., Li, Hui, Ye, Qinghai, Hassan, Manal M., Amin, Hesham M., Kaseb, Ahmed O., Lin, Xin, Wang, Shao-Chun, and Hung, Mien-Chie
- Subjects
Cancer ,Tocilizumab ,Nivolumab ,Regorafenib ,Immunotherapy ,Ruxolitinib ,Sorafenib ,Antibodies ,Siltuximab ,T cells ,Intelligence gathering ,Carcinoma ,Tumors ,Immunoglobulins ,Hepatocellular carcinoma ,Health care industry - Abstract
Glycosylation of immune receptors and ligands, such as T cell receptor and coinhibitory molecules, regulates immune signaling activation and immune surveillance. However, how oncogenic signaling initiates glycosylation of coinhibitory molecules to induce immunosuppression remains unclear. Here we show that IL-6-activated JAK1 phosphorylates programmed death-ligand 1 (PD-L1) Tyr112, which recruits the endoplasmic reticulum-associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability. Targeting of IL-6 by IL-6 antibody induced synergistic T cell killing effects when combined with anti-T cell immunoglobulin mucin-3 (anti-Tim-3) therapy in animal models. A positive correlation between IL-6 and PD-L1 expression was also observed in hepatocellular carcinoma patient tumor tissues. These results identify a mechanism regulating PD-L1 glycosylation initiation and suggest the combination of anti-IL-6 and anti-Tim-3 as an effective marker-guided therapeutic strategy., Introduction Programmed death-ligand 1 (PD-L1; also known as B7 homolog 1 and CD274) is an immune checkpoint protein, and its engagement with programmed cell death protein-1 (PD-1) receptor on T [...]
- Published
- 2019
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