破坏Wnt/β-catenin通路可提高胃癌细胞对PD-1抗体的敏感性

IF 2.4 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jian Li, Hui Zhang, Songhua Bei, Xiaohong Zhang, Huanqing Li, Li Ye, Li Feng
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引用次数: 5

摘要

背景:胃癌(GC)是世界上第五大常见恶性肿瘤和第三大癌症相关死亡原因。免疫检查点抑制剂(ICIs)如程序性细胞死亡-1 (PD-1)抗体在肿瘤治疗中发挥积极作用。最近的一项研究发现Wnt/β-catenin信号通路与肿瘤微环境t细胞浸润(TME)呈负相关,从而影响PD-1抗体的治疗效果。目的:在本研究中,我们旨在揭示Wnt/β-catenin通路与CD8+ T细胞活性的关系及其对GC抗pd -1治疗效果的影响。方法和结果:我们首先收集临床样本并进行免疫组织化学分析,发现GC组织中β-catenin的高表达往往与CD8+ t细胞浸润的明显缺失有关。此外,我们的数据进一步表明,GC细胞中Wnt/β-catenin通路的破坏会抑制其迁移和侵袭能力。同时,在Wnt/β-catenin通路抑制的肿瘤和Jurkat细胞共培养系统中,Jurkat细胞凋亡率降低,GC细胞凋亡率升高,表明GC细胞对PD-1阻断治疗的敏感性增强。结论:综上所述,Wnt/β-catenin通路可能在Jurkat细胞活性调节中发挥重要作用,下调Wnt/β-catenin可增强GC细胞对PD-1抗体的体外敏感性。这一结果进一步表明β-catenin和PD-1靶向抑制可能成为一种潜在有效的治疗GC患者的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Disruption of Wnt/β-catenin Pathway Elevates the Sensitivity of Gastric Cancer Cells to PD-1 Antibody.

Background: Gastric Cancer (GC) is the fifth most common malignancy tumor and the third cause of cancer-related death around the world. Immune checkpoint inhibitors (ICIs) such as programmed cell death-1 (PD-1) antibodies play an active role in tumor therapy. A recent study reveals that Wnt/β-catenin signaling pathway is negatively correlated with T-cell infiltration in tumor microenvironment (TME), thereby influencing the therapeutic efficacy of PD-1 antibody.

Objective: In this study, we aimed to uncover the relationship of Wnt/β-catenin pathway to CD8+ T cell activity as well as its effect on anti-PD-1 therapeutic efficacy in GC.

Methods and results: We first collected clinical samples and went through an immunohistochemical analysis and found that a high β-catenin expression in GC tissues was often associated with a significant absence of CD8+ T-cell infiltration. In addition, our data further indicated that disruption of the Wnt/β-catenin pathway in GC cells inhibited their migratory and invasive ability. Meanwhile, enhanced sensitivity of GC cells to PD-1 blockade therapy was evident by decreased Jurkat cell apoptosis rate and increased GC cell apoptosis rate in a tumor and Jurkat cells co-culture system with the presence of Wnt/β-catenin pathway inhibition.

Conclusion: Collectively, these findings indicated Wnt/β-catenin pathway may play a significant role in modulating the activity of Jurkat cells and downregulation of Wnt/β-catenin may enhance the sensitivity of GC cells to PD-1 antibody in vitro. This result further indicated that β-catenin and PD-1 targeted inhibition might become a potential and effective therapy for GC patients.

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来源期刊
Current molecular pharmacology
Current molecular pharmacology Pharmacology, Toxicology and Pharmaceutics-Drug Discovery
CiteScore
4.90
自引率
3.70%
发文量
112
期刊介绍: Current Molecular Pharmacology aims to publish the latest developments in cellular and molecular pharmacology with a major emphasis on the mechanism of action of novel drugs under development, innovative pharmacological technologies, cell signaling, transduction pathway analysis, genomics, proteomics, and metabonomics applications to drug action. An additional focus will be the way in which normal biological function is illuminated by knowledge of the action of drugs at the cellular and molecular level. The journal publishes full-length/mini reviews, original research articles and thematic issues on molecular pharmacology. Current Molecular Pharmacology is an essential journal for every scientist who is involved in drug design and discovery, target identification, target validation, preclinical and clinical development of drugs therapeutically useful in human disease.
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