College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
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.
Eur J Immunol. 2020 Nov;50(11):1820-1833. doi: 10.1002/eji.202048543. Epub 2020 Sep 3.
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.
作为免疫检查点，程序性细胞死亡蛋白 1（PD-1）及其配体（PD-L1）途径在 CD8 细胞毒性 T 淋巴细胞（CTL）的激活中起着至关重要的作用，并提供抗肿瘤反应。PD-1 和 PD-L1 的 N-糖基高度核心岩藻糖化，这仅由核心岩藻糖基转移酶（Fut8）催化。然而，PD-1 和 PD-L1 的核心岩藻糖化对 CTL 激活的影响的确切生物学机制尚未完全了解。在这项研究中，我们发现核心岩藻糖化在肺腺癌中显著上调。与 Fut8 OT-I 小鼠相比，在 Fut8 OT-I 小鼠中，由尿烷诱导的肺腺癌形成明显减少。PD-1 的去核心岩藻糖化削弱了其在 Fut8 CTL 上的表达，导致 Fut8 CTL 的激活和细胞毒性增强，从而更有效地清除肿瘤。事实上，核心岩藻糖化的缺失显著增强了 PD-1 的泛素化，进而导致 PD-1 在蛋白酶体中的降解。我们目前的工作表明，抑制核心岩藻糖化是未来抗肺腺癌免疫治疗中降低 PD-1 表达的一种独特策略。
