期刊
FRONTIERS IN ONCOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2022.815437
关键词
TGF-beta 1; PD-L1; glycosylation; nasopharyngeal carcinoma; immunotherapy
类别
资金
- National Natural Science Foundation of China [81472535]
- Natural Science Foundation of Guangdong Province, China [2019A1515010968]
N-glycosylation of PD-L1 in nasopharyngeal carcinoma (NPC) is regulated by the TGF-beta 1 activated c-Jun/STT3A signaling pathway, which affects immune evasion and reduces the efficacy of cancer immunotherapy.
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-beta 1 could positively regulate STT3A expression through activating c-Jun to bind to STT3A promoter. Functional assays showed that inhibition of TGF-beta 1 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-beta 1 and c-Jun, and high STT3A expression was positively correlated with a more advanced clinical stage. Altogether, TGF-beta 1 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-beta 1 pathway might be a promising approach to enhance immune checkpoint blockade, and simultaneous blockade of PD-L1 and TGF-beta 1 pathways might elicit potent and superior antitumor activity relative to monotherapies.
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