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

doi:10.1172/JCI126022

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 NieJennifer 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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205 Scopus citations

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.

Original language	English (US)
Pages (from-to)	3324-3338
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	129
Issue number	8
DOIs	https://doi.org/10.1172/JCI126022
State	Published - Aug 1 2019

ASJC Scopus subject areas

General Medicine

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Chan, L. C., Li, C. W., Xia, W., Hsu, J. M., Lee, H. H., Cha, J. H., Wang, H. L., Yang, W. H., Yen, E. Y., Chang, W. C., Zha, Z., Lim, S. O., Lai, Y. J., Liu, C., Liu, J., Dong, Q., Yang, Y., Sun, L., Wei, Y., ... Hung, M. C. (2019). IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. Journal of Clinical Investigation, 129(8), 3324-3338. https://doi.org/10.1172/JCI126022

Chan, LC, Li, CW, Xia, W, Hsu, JM, Lee, HH, Cha, JH, Wang, HL, Yang, WH, Yen, EY, Chang, WC, Zha, Z, Lim, SO, Lai, YJ, Liu, C, Liu, J, Dong, Q, Yang, Y, Sun, L, Wei, Y , Nie, L, Hsu, JL, Li, H, Ye, Q, Hassan, MM , Amin, HM , Kaseb, AO, Lin, X, Wang, SC & Hung, MC 2019, 'IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion', Journal of Clinical Investigation, vol. 129, no. 8, pp. 3324-3338. https://doi.org/10.1172/JCI126022

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title = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",

year = "2019",

month = aug,

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doi = "10.1172/JCI126022",

language = "English (US)",

volume = "129",

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T1 - IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion

AU - Chan, Li Chuan

AU - Li, Chia Wei

AU - Xia, Weiya

AU - Hsu, Jung Mao

AU - Lee, Heng Huan

AU - Cha, Jong Ho

AU - Wang, Hung Ling

AU - Yang, Wen Hao

AU - Yen, Er Yen

AU - Chang, Wei Chao

AU - Zha, Zhengyu

AU - Lim, Seung Oe

AU - Lai, Yun Ju

AU - Liu, Chunxiao

AU - Liu, Jielin

AU - Dong, Qiongzhu

AU - Yang, Yi

AU - Sun, Linlin

AU - Wei, Yongkun

AU - Nie, Lei

AU - Hsu, Jennifer L.

AU - Li, Hui

AU - Ye, Qinghai

AU - Hassan, Manal M.

AU - Amin, Hesham M.

AU - Kaseb, Ahmed O.

AU - Lin, Xin

AU - Wang, Shao Chun

AU - Hung, Mien Chie

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

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SN - 0021-9738

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SP - 3324

EP - 3338

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 8

ER -

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

Abstract

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