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

被引：286

作者：

Chan, Li-Chuan ^{[1
,2
]}

Li, Chia-Wei ^{[1
]}

Xia, Weiya ^{[1
]}

Hsu, Jung-Mao ^{[1
]}

Lee, Heng-Huan ^{[1
]}

Cha, Jong-Ho ^{[1
,3
]}

Wang, Hung-Ling ^{[4
,5
]}

Yang, Wen-Hao ^{[1
]}

Yen, Er-Yen ^{[2
]}

Chang, Wei-Chao ^{[4
,5
]}

Zha, Zhengyu ^{[1
]}

Lim, Seung-Oe ^{[1
]}

Lai, Yun-Ju ^{[6
]}

Liu, Chunxiao ^{[1
]}

Liu, Jielin ^{[1
,2
]}

Dong, Qiongzhu ^{[1
,7
,8
,9
]}

Yang, Yi ^{[1
]}

Sun, Linlin ^{[1
,10
]}

Wei, Yongkun ^{[1
]}

Nie, Lei ^{[1
]}

Hsu, Jennifer L. ^{[1
,4
,5
,11
]}

Li, Hui ^{[1
,12
,13
]}

Ye, Qinghai ^{[12
,13
]}

Hassan, Manal M. ^{[14
]}

Amin, Hesham M. ^{[15
]}

Kaseb, Ahmed O. ^{[14
]}

Lin, Xin ^{[16
]}

Wang, Shao-Chun ^{[4
,5
]}

Hung, Mien-Chie ^{[1
,2
,4
,5
,11
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[2] Univ Texas Hlth Sci Ctr Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA

[3] Seoul Natl Univ, Coll Pharm, Tumor Microenvironm Global Core Res Ctr, Seoul, South Korea

[4] China Med Univ, Grad Inst Biomed Sci, Taichung, Taiwan

[5] China Med Univ, Ctr Mol Med, Taichung, Taiwan

[6] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Neurol, Houston, TX 77030 USA

[7] Fudan Univ, Huashan Hosp, Dept Gen Surg, Shanghai, Peoples R China

[8] Fudan Univ, Canc Metastasis Inst, Shanghai, Peoples R China

[9] Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China

[10] Tianjin Med Univ, Gen Hosp, Lung Canc Inst, Tianjin Key Lab Lung Canc Metastasis & Tumor Micr, Tianjin, Peoples R China

[11] Asia Univ, Dept Biotechnol, Taichung, Taiwan

[12] Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Shanghai, Peoples R China

[13] Minist Educ, Key Lab Carcinogenesis & Canc Invas, Shanghai, Peoples R China

[14] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA

[15] Univ Texas MD Anderson Canc Ctr, Div Pathol & Lab Med, Dept Hematopathol, Houston, TX 77030 USA

[16] Tsinghua Univ, Sch Med, Inst Immunol, Beijing, Peoples R China

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2019年 / 129卷 / 08期

基金：

新加坡国家研究基金会;

关键词：

HEPATOCELLULAR-CARCINOMA; ACQUIRED-RESISTANCE; POOR-PROGNOSIS; TUMOR-CELLS; CHECKPOINT; EXPRESSION; BLOCKADE; IL-6; IDENTIFICATION; GLYCOSYLATION;

D O I：

10.1172/JCI126022

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：3324 / 3338

页数：15

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