| Affiliation: | 1. College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China These two authors contributed equally to this work.;2. Tianjin Medical University Cancer Institute and Hospital. National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin. Tianjin's Clinical Research Center for Cancer, Tianjin, China;3. College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China;4. Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China;5. Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan |
| 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. |
