Triple‐negative breast cancer (TNBC) lacks a well‐defined molecular target and is associated with poorer outcomes compared to other breast cancer subtypes. Programmed cell death protein 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) blockade therapy shows a 10% to 20% response rate in TNBC patients. Our previous studies show that PD‐L1 proteins are heavily glycosylated in TNBC, and the glycosylation plays an important role in the PD‐L1 protein's stability and immunosuppressive function. However, a strategy for PD‐L1 deglycosylation in TNBC is poorly defined. Here we found that a saccharide analog, 2‐deoxy‐ d ‐glucose (2‐DG), inhibits glycosylation of PD‐L1 and its immunosuppressive function by combining with EGFR inhibitor, gefitinib. Interestingly, 2‐DG/gefitinib‐induced deglycosylation of PD‐L1 decreased the expression level of PD‐L1 protein as well as its binding with PD‐1. However, there was no significant decrease in 4‐1BB expression and its binding with 4‐1BBL by 2‐DG/gefitinib. Furthermore, we demonstrated that the combination treatment of 2‐DG/gefitinib and 4‐1BB antibody enhances antitumor immunity in TNBC syngeneic murine models. Together, our results suggest a new immunotherapeutic strategy to enhance antitumor immunity by PD‐L1 deglycosylation and 4‐1BB stimulation in TNBC.

中文翻译：

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糖化物类似物2-deoxy-d-glucose通过PD-L1去糖基化增强4-1BB介导的抗肿瘤免疫力。

与其他乳腺癌亚型相比，三阴性乳腺癌（TNBC）缺乏明确的分子靶标，并且预后较差。程序性细胞死亡蛋白1（PD-1）/程序性死亡配体1（PD-1L）阻断疗法在TNBC患者中显示出10％至20％的缓解率。我们以前的研究表明，PD-L1蛋白在TNBC中被高度糖基化，而糖基化在PD-L1蛋白的稳定性和免疫抑制功能中起着重要作用。但是，对于TNBC中PD-L1去糖基化的策略定义不明确。在这里，我们发现，糖类模拟，2-脱氧 d葡萄糖（2-DG）通过与EGFR抑制剂吉非替尼联合使用来抑制PD-L1的糖基化及其免疫抑制功能。有趣的是，2-DG /吉非替尼诱导的PD-L1的去糖基化降低了PD-L1蛋白的表达水平以及与PD-1的结合。但是，2-DG /吉非替尼对4-1BB的表达及其与4-1BBL的结合没有显着降低。此外，我们证明了将2-DG /吉非替尼和4-1BB抗体联合治疗可增强TNBC同系小鼠模型的抗肿瘤免疫力。总之，我们的结果提出了一种新的免疫治疗策略，通过TNBC中的PD-L1去糖基化和4-1BB刺激来增强抗肿瘤免疫力。