University of Texas Health Science Center at Houston
Il-6/Jak1 Drives Pd-L1 Phosphorylation and Glycosylation to Promote Cancer Immune Evasion
Abstract
dc:description.abstract<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>
Degree
thesis:*- Name thesis:degree_name
- Doctor of Philosophy (PhD)
- Level thesis:degree_level
- Dissertation (PhD)
- Year dc:date.available
- 2019
Author and committee
dc:creator, dc:contributor.*- Authors dc:creator
-
- Chan, Li-Chuan
- <p>https://orcid.org/0000-0002-2665-637X</p>
- Contributors dc:contributor
-
- Mien-Chie Hung, Ph.D
- Paul J. Chiao, Ph.D.
- Ahmed Kaseb, M.D.
Subjects
dc:subject × 4Identifiers
dc:identifier.*- Repository record dc:identifier
- https://digitalcommons.library.tmc.edu/utgsbs_dissertations/933
- OAI identifier oai:identifier
- oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1978