基于PD-1/PD-L1通路的核心岩藻糖基化修饰调节细胞毒性T淋巴细胞杀伤非小细胞肺癌的作用机理研究

As an important immune checkpoint, pathway of programmed cell death 1 (PD-1) and its ligand (PD-L1) plays a crucial role in CD8+ cytotoxic T lymphocytes (CTL) activation and its tumor eradication. PD-1 and PD-L1 are highly core fucosylated glycoproteins. Core fucosylation on N-glycans of glycoprotein was only catalyzed by core fucosyltransferase (Fut8). In our previous study, we found that the signal transduction was significantly enhanced in the Fut8-/-OT-I CTL by Fut8 gene ablation. Moreover, compared to the Fut8+/+OT-I CTL, the ability of NSCLC tumor killing was markedly enhanced in Fut8-/-OT-I CTL. Interestingly, the level of core fucosylation was significantly up-regulated in the sera and cancer tissue of NSCLC patients. However, the precise biochemical mechanisms for the high core fucosylation of PD-1 and PD-L1 on CTL activation and its tumor eradication have not been fully understood. To investigate the role of Fut8 in the CTL activation and tumor eradication, we established the several interaction models between CTL and lung cancer cells using clinical samples for NSCLC, Fut8 knockout mice and Fut8 knockdown CTL cell line. Our results will lay a foundation for further understanding the specific process of anti-NSCLC immune therapy from the new perspective of core fucosylation modifications.

作为重要免疫检查点，程序性死亡受体1(PD-1)及其配体PD-L1通路在CD8+细胞毒性T淋巴细胞(CTL)活化及肿瘤杀伤过程中发挥重要作用。PD-1及PD-L1是高度核心岩藻糖基化的糖蛋白。核心岩藻糖基转移酶(Fut8)负责催化核心岩藻糖基修饰。我们发现，核心岩藻糖基缺损使CTL细胞表面PD-1表达量显著减少，并促进CTL活化；与Fut8+/+OT-I CTL相比，Fut8-/-OT-I CTL杀伤肿瘤细胞作用显著增强；在非小细胞肺癌(NSCLC)微环境中核心岩藻糖基化水平明显增高，推测PD-1/PD-L1核心岩藻糖基化与CTL杀伤NSCLC作用密切相关。本课题拟利用NSCLC临床样品、Fut8-/-OT-I小鼠及Fut8基因沉默CTL细胞株，建立各种CTL-NSCLC相互作用模型，研究核心岩藻糖基对PD-1/PD-L1通路及CTL杀伤NSCLC作用机理，为NSCLC免疫治疗提供新思路。

作为重要免疫检查点，PD-1及其配体PD-L1通路在CD8+细胞毒性T淋巴细胞(CTL)活化及肿瘤杀伤过程中发挥重要作用。PD-1及PD-L1是高度核心岩藻糖基化的糖蛋白。核心岩藻糖基转移酶(Fut8)负责催化核心岩藻糖基修饰。我们发现，核心岩藻糖基缺损使CTL细胞表面PD-1表达量显著减少，并促进CTL活化；与Fut8+/+OT-I CTL相比，Fut8-/-OT-I CTL杀伤肿瘤细胞作用显著增强；在非小细胞肺癌(NSCLC)微环境中核心岩藻糖基化水平明显增高。PD-1/PD-L1核心岩藻糖基化与CTL杀伤NSCLC作用密切相关。相关数据在Front Immunol 2022  (IF=8.786), Cell Death Disease 2021 (IF=9.685) , Brain Res Bull. 2021 (IF=4.077), Journal of Microbiology Immunology and Infection 2021 (IF=10.273), European Journal of Immunology 2020 (IF=5.532) Faseb Journal. 2020 (IF=5.191) , Frontiers in Microbiology 2020 (IF=5.64) , Scientific Reports 2020 (IF= 4.379), Biochemical Journal 2020 (IF=4.097) , Immunology Letters 2019 (IF=3.276), Molecular Immunology 2019 (IF=3.641), Molecular Carcinogenesis 2019 (IF=3.851), mbio 2019 (IF= 6.747) , Adv Exp Med Biol 2019 (IF=2.09) 等杂志上发表；并申请1项国内专利（一种核心岩藻糖基转移酶的抑制剂及其应用20211180422.8）。本课题利用NSCLC临床样品、Fut8-/-OT-I小鼠及Fut8基因沉默CTL细胞株，建立各种CTL-NSCLC相互作用模型，研究核心岩藻糖基对PD-1/PD-L1通路及CTL杀伤NSCLC作用机理，为NSCLC免疫治疗提供新思路。