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TGF-β1-Mediated PD-L1 Glycosylation Contributes to Immune Escape via c-Jun/STT3A Pathway in Nasopharyngeal Carcinoma
- Source :
- Frontiers in Oncology, Vol 12 (2022)
- Publication Year :
- 2022
- Publisher :
- Frontiers Media S.A., 2022.
-
Abstract
- Immunotherapy targeting programmed death ligand-1/programmed cell death protein-1 (PD-L1/PD-1) has achieved great success in multiple cancers, but only a small subset of patients showed clinical responses. Recent evidences have shown that post-translational modification of PD-L1 protein could regulate its protein stability and interaction with cognate receptor PD-1, thereby affecting anticancer immunotherapy in several solid tumors. However, the molecular mechanisms underlying how PD-1/PD-L1 expression is regulated still remain unclear in nasopharyngeal carcinoma (NPC). Here, we found N-glycosylation of PD-L1 in NPC cells and tissues. Mechanistically, we showed that STT3A transferred N-linked glycans to PD-L1, and TGF-β1 could positively regulate STT3A expression through activating c-Jun to bind to STT3A promoter. Functional assays showed that inhibition of TGF-β1 resulted in a decrease of glycosylated PD-L1 and enhanced cytotoxic T-cell function against NPC cells. Analysis of clinical specimens revealed that the expression of STT3A was positively correlated with TGF-β1 and c-Jun, and high STT3A expression was positively correlated with a more advanced clinical stage. Altogether, TGF-β1 activated c-Jun/STT3A signaling pathway to promote N-glycosylation of PD-L1, thus further facilitating immune evasion and reducing the efficacy of cancer immunotherapy. As such, all these data suggested that targeting TGF-β1 pathway might be a promising approach to enhance immune checkpoint blockade, and simultaneous blockade of PD-L1 and TGF-β1 pathways might elicit potent and superior antitumor activity relative to monotherapies.
Details
- Language :
- English
- ISSN :
- 2234943X
- Volume :
- 12
- Database :
- Directory of Open Access Journals
- Journal :
- Frontiers in Oncology
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.58a729c9320146dd8f37380ba7798184
- Document Type :
- article
- Full Text :
- https://doi.org/10.3389/fonc.2022.815437