Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion
Li-Chuan Chan, … , Shao-Chun Wang, Mien-Chie Hung
Li-Chuan Chan, … , Shao-Chun Wang, Mien-Chie Hung
Published July 15, 2019
Citation Information: J Clin Invest. 2019;129(8):3324-3338. https://doi.org/10.1172/JCI126022.
View: Text | PDF
Research Article Cell biology Oncology

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

  • Text
  • PDF
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

×

Figure 3

Anti–IL-6 and anti–Tim-3 combination therapy enhances the activity of cytotoxic CD8+ T cells in the tumor microenvironment and prolongs the survival rate of tumor-bearing mice.

Options: View larger image (or click on image) Download as PowerPoint
Anti–IL-6 and anti–Tim-3 combination therapy enhances the activity of cy...
(A) Representative images of immunofluorescence staining for PD-L1, CD8, and granzyme B (GB) expressions in tumor regions in mice given the indicated treatment. Scale bar: 200 μm. Magnified images showing colocalization of CD8 and granzyme B signals. Scale bar: 50 μm. (B) The percentage of granzyme B–positive CD3+CD8+ T cells in Hepa 1-6 tumors with the indicated treatments according to flow cytometry analysis (n = 7). (C) Percentage of IFN-γ–positive CD3+CD8+ T cells in tumor samples obtained from Hepa 1-6 tumor–bearing mice given the indicated treatments (n = 6). (D) Survival curves for the data shown in Figure 2B. Error bars represent ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, 1-way ANOVA (B and C) and log-rank (Mantel-Cox) test (D).
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts