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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 2

Blocking IL-6/JAK1–mediated PD-L1 protein stability enhances the efficacy of anti–Tim-3 immunotherapy.

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Blocking IL-6/JAK1–mediated PD-L1 protein stability enhances the efficac...
(A) Schematic of the treatment schedule for the IL-6 and Tim-3 monoclonal antibody (mAb) combination therapy. (B) Growth of Hepa 1-6 tumors in mice treated with IL-6 mAb, Tim-3 mAb, or the combination. The number of mice that experienced tumor progression in each group is shown in parentheses. The gray box in each panel indicates the duration of treatment. (C) Representative images showing tumors harvested from mice bearing Hepa 1-6 tumors given IL-6 mAb, Tim-3 mAb, or the combination. Scale bar: 1 cm. (D) Weight of Hepa 1-6 tumors in mice given an IL-6 mAb, Tim-3 mAb, or both (n = 6). (E) Flow cytometric analysis of cell surface PD-L1 expression in Hepa 1-6 tumor region (non-CD45+ population) treated with the indicated regimens (n = 7). Relative fold change in the mean fluorescence intensity (MFI) of PD-L1 is shown. Error bars represent ± SD. **P < 0.01, ****P < 0.0001, 1-way ANOVA (D and E).

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

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