Glycosylation of immune receptors and ligands, such as T-cell receptor (TCR), major histocompatibility complex (MHC), and co-inhibitory molecules, regulates immune signaling activation, antigen presentation, and immune surveillance. Recent studies revealed that the glycan structures of co-inhibitory molecules are required for receptor-ligand interaction, a critical feature for activating cancer immune evasion. However, it is unclear how oncogenic signaling initiates glycosylation of co-inhibitory molecules to induce immunosuppression. Here we show interleukin (IL)-6-activated Janus kinase 1 (JAK1) phosphorylates programmed death-ligand 1 (PD-L1)-Tyr112, leading to the recruitment of endoplasmic reticulum (ER)-associated N-glycosyltransferase, STT3A, which catalyzes the glycosylation of PD-L1, contributing to its stability. A positive correlation between IL-6 and PD-L1 expression levels was observed in tumor samples from patients with hepatocellular carcinoma (HCC). Furthermore, IL-6 blockade led to downregulation of PD-L1 and increased sensitivity to anti-T-cell immunoglobulin mucin-3 (Tim-3) immune checkpoint therapies in animal models. These results identify a mechanism regulating initiation of PD-L1 glycosylation and suggest that the combination of anti-IL-6 and anti-Tim-3 is an effective, biomarker-driven, therapeutic strategy in HCC.
","abstract_html":"<p>Glycosylation of immune receptors and ligands, such as T-cell receptor (TCR), major histocompatibility complex (MHC), and co-inhibitory molecules, regulates immune signaling activation, antigen presentation, and immune surveillance. Recent studies revealed that the glycan structures of co-inhibitory molecules are required for receptor-ligand interaction, a critical feature for activating cancer immune evasion. However, it is unclear how oncogenic signaling initiates glycosylation of co-inhibitory molecules to induce immunosuppression. Here we show interleukin (IL)-6-activated Janus kinase 1 (JAK1) phosphorylates programmed death-ligand 1 (PD-L1)-Tyr112, leading to the recruitment of endoplasmic reticulum (ER)-associated N-glycosyltransferase, STT3A, which catalyzes the glycosylation of PD-L1, contributing to its stability. A positive correlation between IL-6 and PD-L1 expression levels was observed in tumor samples from patients with hepatocellular carcinoma (HCC). Furthermore, IL-6 blockade led to downregulation of PD-L1 and increased sensitivity to anti-T-cell immunoglobulin mucin-3 (Tim-3) immune checkpoint therapies in animal models. These results identify a mechanism regulating initiation of PD-L1 glycosylation and suggest that the combination of anti-IL-6 and anti-Tim-3 is an effective, biomarker-driven, therapeutic strategy in HCC.</p>","abstract_has_math":false,"creators":["Chan, Li-Chuan","https://orcid.org/0000-0002-2665-637X
"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Mien-Chie Hung, Ph.D","Paul J. Chiao, Ph.D.","Ahmed Kaseb, M.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-05-01T07:00:00Z","date_published":"2019-05-01T07:00:00Z","updated_at":"2026-07-24T05:49:30Z","subjects":["IL-6; PD-L1; tyrosine phosphorylation; glycosylation; hepatocellular carcinoma","Cancer Biology","Immunity","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/933","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Mien-Chie Hung, Ph.D","Paul J. Chiao, Ph.D.","Ahmed Kaseb, M.D."]},{"key":"dc:creator","label":"Author","values":["Chan, Li-Chuan","https://orcid.org/0000-0002-2665-637X
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"]},{"key":"dc:title","label":"Title","values":["Il-6/Jak1 Drives Pd-L1 Phosphorylation and Glycosylation to Promote Cancer Immune Evasion"]}]}],"canonical_facts":{"dc:contributor":["Mien-Chie Hung, Ph.D","Paul J. Chiao, Ph.D.","Ahmed Kaseb, M.D."],"dc:creator":["Chan, Li-Chuan","https://orcid.org/0000-0002-2665-637X
"],"dc:date.available":["2020-05-02T07:00:00Z"],"dc:description.abstract":["Glycosylation of immune receptors and ligands, such as T-cell receptor (TCR), major histocompatibility complex (MHC), and co-inhibitory molecules, regulates immune signaling activation, antigen presentation, and immune surveillance. Recent studies revealed that the glycan structures of co-inhibitory molecules are required for receptor-ligand interaction, a critical feature for activating cancer immune evasion. However, it is unclear how oncogenic signaling initiates glycosylation of co-inhibitory molecules to induce immunosuppression. Here we show interleukin (IL)-6-activated Janus kinase 1 (JAK1) phosphorylates programmed death-ligand 1 (PD-L1)-Tyr112, leading to the recruitment of endoplasmic reticulum (ER)-associated N-glycosyltransferase, STT3A, which catalyzes the glycosylation of PD-L1, contributing to its stability. A positive correlation between IL-6 and PD-L1 expression levels was observed in tumor samples from patients with hepatocellular carcinoma (HCC). Furthermore, IL-6 blockade led to downregulation of PD-L1 and increased sensitivity to anti-T-cell immunoglobulin mucin-3 (Tim-3) immune checkpoint therapies in animal models. These results identify a mechanism regulating initiation of PD-L1 glycosylation and suggest that the combination of anti-IL-6 and anti-Tim-3 is an effective, biomarker-driven, therapeutic strategy in HCC.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/933"],"dc:subject":["IL-6; PD-L1; tyrosine phosphorylation; glycosylation; hepatocellular carcinoma","Cancer Biology","Immunity","Medicine and Health Sciences"],"dc:title":["Il-6/Jak1 Drives Pd-L1 Phosphorylation and Glycosylation to Promote Cancer Immune Evasion"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:30Z"}