Protein glycosylation provides proteomic diversity in regulating protein localization, stability, and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD-L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces a potent cell-killing effect as well as a bystander-killing effect on adjacent cancer cells lacking PD-L1 expression without any detectable toxicity. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy.

中文翻译：

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通过靶向糖基化的PD-L1消灭三阴性乳腺癌细胞。

蛋白质糖基化在调节蛋白质的定位，稳定性和活性方面提供了蛋白质组学多样性。糖部分是否有助于免疫抑制仍是很大程度上未知的。在免疫受体糖基化研究中，我们发现EGF诱导程序性死亡配体1（PD-L1）和受体程序性细胞死亡蛋白1（PD-1）相互作用，需要β-1,3-N-乙酰氨基葡萄糖基转移酶（B3GNT3）在三阴性乳腺癌中的表达。B3GNT3的下调增强了细胞毒性T细胞介导的抗肿瘤免疫力。靶向糖基化PD-L1（gPD-L1）的单克隆抗体可阻止PD-L1 / PD-1相互作用，并促进PD-L1的内在化和降解。除了免疫激活，药物偶联的gPD-L1抗体对缺乏PD-L1表达但没有可检测的毒性的相邻癌细胞产生有效的细胞杀伤作用以及旁观者杀伤作用。我们的工作建议将蛋白质糖基化作为增强免疫检查点治疗的潜在策略。