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

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 1

The IL-6/JAK1 pathway positively regulates PD-L1 protein stability, and IL-6 and PD-L1 expression is positively correlated in tumor tissues from HCC patients.

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The IL-6/JAK1 pathway positively regulates PD-L1 protein stability, and ...
(A) Schematic of the strategy using the indicated criteria (1, 2, and 3) to identify pathways that potentially upregulate PD-L1 expression via posttranslational modifications. (B) Western blot (WB) analysis of exogenous PD-L1 expression in FLAG–PD-L1 WT–Hep 3B and WT–SK-HEP-1 cells stimulated with different cytokines for 18 hours. (C) WB analysis of exogenous PD-L1 expression in FLAG–PD-L1 WT–Hep 3B and WT–SK-HEP-1 cells under IL-6 stimulation (20 ng/mL) or cotreatment with the JAK1/2 inhibitor ruxolitinib (10 μmol/L) for 18 hours. (D) WB analysis of exogenous PD-L1 expression in FLAG–PD-L1 WT–Hep 3B cells with IL-6 stimulation (20 ng/mL) or cotreatment with ruxolitinib (10 μmol/L) for the indicated times. SE, short exposure; LE, long exposure. (E) WB analysis of exogenous PD-L1 expression in the presence or absence of IL-6 stimulation (20 ng/mL, 18 hours), ruxolitinib (10 μmol/L, 18 hours), or the proteasome inhibitor MG132 (10 μmol/L, 6 hours). (F) WB analysis of exogenous PD-L1 expression in FLAG–PD-L1 WT–SK-HEP-1 and WT–Hep 3B cells with knockdown of the indicated genes by siRNA. (G) Representative images of IL-6 and PD-L1 expression levels in tumor regions in HCC patients. Original magnification, ×400.