Author ORCID Identifier

Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Mien-Chie Hung, Ph.D

Committee Member

Paul J. Chiao, Ph.D.

Committee Member

Ahmed Kaseb, M.D.

Committee Member

Chunru Lin, Ph.D.

Committee Member

Jeffrey T. Chang, Ph.D.


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.


IL-6; PD-L1; tyrosine phosphorylation; glycosylation; hepatocellular carcinoma



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