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IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion
Li-Chuan Chan, … , Shao-Chun Wang, Mien-Chie Hung
Li-Chuan Chan, … , Shao-Chun Wang, Mien-Chie Hung
Published July 15, 2019
Citation Information: J Clin Invest. 2019;129(8):3324-3338. https://doi.org/10.1172/JCI126022.
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Research Article Cell biology Oncology

IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion

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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.

Authors

Li-Chuan Chan, Chia-Wei Li, Weiya Xia, Jung-Mao Hsu, Heng-Huan Lee, Jong-Ho Cha, Hung-Ling Wang, Wen-Hao Yang, Er-Yen Yen, Wei-Chao Chang, Zhengyu Zha, Seung-Oe Lim, Yun-Ju Lai, Chunxiao Liu, Jielin Liu, Qiongzhu Dong, Yi Yang, Linlin Sun, Yongkun Wei, Lei Nie, Jennifer L. Hsu, Hui Li, Qinghai Ye, Manal M. Hassan, Hesham M. Amin, Ahmed O. Kaseb, Xin Lin, Shao-Chun Wang, Mien-Chie Hung

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Figure 10

A proposed model illustrating PD-L1 protein Y112 phosphorylation, glycosylation initiation, and stability regulated by the IL-6/JAK1 signaling pathway in cancer immune escape.

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A proposed model illustrating PD-L1 protein Y112 phosphorylation, glycos...
Under IL-6 stimulation, JAK1 interacts with and phosphorylates nonglycosylated PD-L1 at Y112 in tumor cells, which enhances the association with STT3A for glycosylation initiation. Blocking the IL-6/JAK1 pathway leads to the loss of PD-L1 stability and sensitizes tumor cells to anti–Tim-3 immune checkpoint therapy.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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