IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion
IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion
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DOI：
10.1172/jci126022
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发表时间：
2019-08-01
影响因子：
15.9
通讯作者：
Hung, Mien-Chie
中科院分区：
文献类型：
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作者：
Chan, Li-Chuan;Li, Chia-Wei;Hung, Mien-Chie
免疫受体和配体的糖基化，如T细胞受体和共抑制分子，调节免疫信号的激活和免疫监视。然而，致癌信号如何启动共抑制分子的糖基化以诱导免疫抑制仍不清楚。在这里，我们证明了IL-6激活的JAK1磷酸化程序性死亡配体1(PD-L1)Tyr112，从而招募内质网相关的N-糖基转移酶STT3A来催化PD-L1糖基化，维持PD-L1的稳定性。在动物模型中，IL-6抗体靶向IL-6与抗T细胞免疫球蛋白粘蛋白-3(anti-Tim-3)联合治疗时，可诱导协同T细胞杀伤效应。肝细胞癌组织中IL-6和PD-L1的表达也呈正相关。这些结果确定了调节PD-L1糖基化启动的机制，并提示联合使用抗IL-6和抗TIM-3是一种有效的标记物导向治疗策略。
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.