分割GlcNAc可通过抑制PD-L1的表达及其与PD-1的结合来增强CD8+ T细胞介导的乳腺癌杀伤。

IF 13.5 1区 医学 Q1 HEMATOLOGY
Xueting Ren, Jinpeng Wu, Jing Li, Zhen Zhai, Xiang Li, Feng Guan, Meng Wang, Xiaobin Ma, Zengqi Tan, Huafeng Kang, Shuai Lin
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引用次数: 0

摘要

背景:肿瘤细胞表面PD-L1的丰度是使这些细胞对T细胞介导的免疫杀伤敏感的关键因素。虽然已知PD-L1的异常糖基化会影响其表达和功能,但确切的调节机制尚不清楚。方法:本研究利用生物信息学分析方法,探讨参与分割GlcNAc结构形成的关键基因MGAT3在乳腺癌(BC)中的作用。采用实验方法提高BC细胞中分割GlcNAc水平,随后评估PD-L1表达、CD8+ T细胞介导的细胞毒性、细胞外囊泡(EV)相关的PD-L1以及PD-L1/PD-1相互作用。此外,将分割GlcNAc激动剂forskolin与抗pd - l1抗体联合在体内评价其抗肿瘤作用。结果:MGAT3在BC组织中低水平表达,但与CD8+ T细胞浸润呈正相关。升高BC细胞中的GlcNAc水平可显著增强CD8+ T细胞的细胞毒作用。高分割的GlcNAc修饰通过溶酶体途径促进PD-L1降解,降低PD-L1的表达及其与PD-1的结合。此外,增加的分割GlcNAc水平降低了肿瘤细胞源性ev中的PD-L1,削弱了ev阻断CD8+ T细胞的能力,间接增强了T细胞的细胞毒性。联合使用福斯克林和抗pd - l1抗体可显著提高CD8+ T细胞的丰度和活性,实现更有效的体内抗肿瘤反应。结论:这些发现表明,在BC细胞中增强GlcNAc的分割修饰可促进PD-L1降解并抑制其与PD-1的结合,从而增强CD8+ T细胞介导的细胞毒性,为BC治疗中的免疫调节提供了一种有希望的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Bisecting GlcNAc enhances CD8+ T cell-mediated killing of breast cancer by suppressing PD-L1 expression and its binding to PD-1.

Background: The abundance of PD-L1 on the surface of tumor cells is a critical factor in sensitizing these cells to T cell-mediated immune killing. While abnormal glycosylation of PD-L1 is known to influence its expression and function, the precise regulatory mechanisms remain unclear.

Methods: This study utilized bioinformatics analysis to explore the role of MGAT3, a key gene involved in the formation of the bisecting GlcNAc structure, in breast cancer (BC). Experimental approaches were employed to increase bisecting GlcNAc levels in BC cells, followed by assessments of PD-L1 expression, CD8+ T cell-mediated cytotoxicity, extracellular vesicle (EV)-associated PD-L1, and PD-L1/PD-1 interaction. Additionally, forskolin, a bisecting GlcNAc agonist, was combined with anti-PD-L1 antibody to evaluate its antitumor effects in vivo.

Results: MGAT3 was found to be expressed at low levels in BC tissues but positively correlated with CD8+ T cell infiltration. Elevating bisecting GlcNAc levels in BC cells significantly enhanced the cytotoxic efficacy of CD8+ T cells. High bisecting GlcNAc modification promoted PD-L1 degradation via the lysosomal pathway, reducing PD-L1 expression and its binding to PD-1. Furthermore, increased bisecting GlcNAc levels reduced PD-L1 in tumor cell-derived EVs, impairing the EVs' ability to block CD8+ T cells and indirectly enhancing T cell cytotoxicity. The combined use of forskolin and anti-PD-L1 antibody significantly increased CD8+ T cell abundance and activity, achieving a more effective antitumor response in vivo.

Conclusions: These findings demonstrate that enhancing bisecting GlcNAc modification in BC cells promotes PD-L1 degradation and inhibits its binding to PD-1, thereby boosting CD8+ T cell-mediated cytotoxicity, providing a promising strategy for immune modulation in BC therapy.

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来源期刊
CiteScore
12.60
自引率
7.30%
发文量
97
审稿时长
6 weeks
期刊介绍: Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings. Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.
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