Loss of core fucosylation enhances the anticancer activity of cytotoxic T lymphocytes by increasing PD‐1 degradation. Issue 11 (3rd September 2020)

• Record Type: Journal Article
• Authors: Zhang, Nianzhu; Li, Ming; Xu, Xing; Zhang, Yingshu; Liu, Yancheng; Zhao, Meng; Li, Peng; Chen, Jun; Fukuda, Tomohiko; Gu, Jianguo; Jin, Xun; Li, Wenzhe
• Is Part Of: European journal of immunology. Volume 50:Issue 11(2020)
• Page Start: 1820
• Page End: 1833
• Publication Date: 2020-09-03
• Subjects: Core fucosylation -- CTL activation -- Lung adenocarcinoma -- Programmed cell death 1 (PD‐1) -- Ubiquitination; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.202048543
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: As an immune checkpoint, programmed cell death 1 (PD‐1) and its ligand (PD‐L1) pathway plays a crucial role in CD8 + cytotoxic T lymphocytes (CTL) activation and provides antitumor responses. The N ‐glycans of PD‐1 and PD‐L1 are highly core fucosylated, which are solely catalyzed by the core fucosyltransferase (Fut8). However, the precise biological mechanisms underlying effects of core fucosylation of PD‐1 and PD‐L1 on CTL activation have not been fully understood. In this study, we found that core fucosylation was significantly upregulated in lung adenocarcinoma. Compared to those of Fut8 +/+ OT‐I mice, the lung adenocarcinoma formation induced by urethane was markedly reduced in Fut8 −/− OT‐I mice. De‐core fucosylation of PD‐1 compromised its expression on Fut8 −/− CTL, resulted in enhanced Fut8 −/− CTL activation and cytotoxicity, leading to more efficient tumor eradication. Indeed, loss of core fucosylation significantly enhanced the PD‐1 ubiquitination and in turn led to the degradation of PD‐1 in the proteasome. Our current work indicates that inhibition of core fucosylation is a unique strategy to reduce PD‐1 expression for the antilung adenocarcinoma immune therapy in the future. Abstract : De‐core fucosylation enhances the ubiquitination and the degradation of PD‐1. Fut8 ablation promotes the CTL cytotoxic capacity and results in more efficient tumor eradication. These results indicate that de‐core fucosylation is a unique strategy to reduce PD‐1 expression for the anticancer therapy.