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

• Published in: The Journal of clinical investigation Vol. 129; no. 8; pp. 3324 - 3338
• Main Authors: Chan, Li-Chuan, Li, Chia-Wei, Xia, Weiya, Hsu, Jung-Mao, Lee, Heng-Huan, Cha, Jong-Ho, Wang, Hung-Ling, Yang, Wen-Hao, Yen, Er-Yen, Chang, Wei-Chao, Zha, Zhengyu, Lim, Seung-Oe, Lai, Yun-Ju, Liu, Chunxiao, Liu, Jielin, Dong, Qiongzhu, Yang, Yi, Sun, Linlin, Wei, Yongkun, Nie, Lei, Hsu, Jennifer L., Li, Hui, Ye, Qinghai, Hassan, Manal M., Amin, Hesham M., Kaseb, Ahmed O., Lin, Xin, Wang, Shao-Chun, Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2019
• Subjects: Animal models; Animals; Antibodies; Apoptosis; B7-H1 Antigen - immunology; Biomedical research; Cancer; Carcinoma; Cell activation; Cell growth; Cell Line, Tumor; Chemokines; Cytokines; Endoplasmic reticulum; FDA approval; Federal regulation; Gene expression; Glycosylation; Glycosyltransferase; Growth factors; Hepatocellular carcinoma; Humans; Immune evasion; Immunoglobulins; Immunosuppression; Immunosurveillance; Immunotherapy; Intelligence gathering; Interleukin 6; Interleukin-6 - immunology; Janus kinase; Janus Kinase 1 - immunology; Kinases; Ligands; Liver cancer; Lymphocytes; Lymphocytes T; Male; Medical prognosis; Mice; Mucin; Mutation; Neoplasm Proteins - immunology; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Neoplasms, Experimental - therapy; Nivolumab; Patients; PD-L1 protein; Phosphorylation; Protein expression; Protein Stability; Proteins; Regorafenib; Response rates; Ruxolitinib; Signal Transduction - immunology; Siltuximab; Sorafenib; T cell receptors; T cells; Tocilizumab; Tumor Escape; Tumors; South Korea; Texas; China; Liver cancer; Oncology; Cancer immunotherapy; Cell Biology
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI126022

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.