IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion
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
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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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 8

PD-L1 Y112F mutation reduces PD-L1 expression in Hepa 1-6 without affecting tumorigenesis in immunodeficient mice.

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PD-L1 Y112F mutation reduces PD-L1 expression in Hepa 1-6 without affect...
(A) WB analysis of exogenous PD-L1 expression in FLAG–PD-L1 WT or Y112F–Hepa 1-6 cells with or without exposure to IL-6 (20 ng/mL) and/or ruxolitinib (10 μmol/L) for 18 hours. Data show relative fold change of PD-L1 protein normalized to the mock group (1 or 4) in each cell line (n = 3). (B) Tumor growth of PD-L1 WT–Hepa 1-6 or Y112F–Hepa 1-6 cells in immunodeficient (NSG) mice (n = 6). (C) Tumor weight (left) and images of tumors (right) harvested from NSG mice inoculated with PD-L1 WT–Hepa 1-6 or Y112F–Hepa 1-6 cells. Scale bar: 1 cm. (D) Flow cytometric analysis of cell surface PD-L1 expression on PD-L1 WT–Hepa 1-6 or Y112F–Hepa 1-6 tumors (n = 5). The relative fold change in the MFI of PD-L1 is shown. Error bars represent ± SD. ***P < 0.001, ****P < 0.0001, 1-way ANOVA (A), repeated-measures ANOVA (B), and Mann-Whitney test (C and D).