Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 8, Pages 3324-3338Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI126022
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Funding
- NIH/National Cancer Institute [P30CA016672, R01 CA211615, AI116722]
- Cancer Prevention & Research Institute of Texas [RP160710]
- University of Texas MD Anderson Cancer Center-China Medical University
- Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence [MOHW108-TDU-B-212-124024, MOHW108-TDU-B-212-122015]
- Center for Biological Pathways
- Ministry of Science and Technology Overseas Project for Post Graduate Research [MOST 104-2917-I-564-003]
- National Research Foundation of Korea - Korean government [MSIP 2011-0030001]
- MD Anderson Odyssey Fellowship Program
- NIH T32 Training Grant in Cancer Biology [5T32CA186892]
- University of Texas MD Anderson Cancer Center-Hospital Sister Institution Fund
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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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