食管鳞状细胞癌衍生的sEV-PDL1耗尽CD8+T细胞促进免疫抑制。

IF 3.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular immunology Pub Date : 2025-02-01 DOI:10.1016/j.molimm.2025.01.001
Zijie Li , Xiaokuan Zhang , Yuying Qi , Zhiyu Wang
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引用次数: 0

摘要

食管鳞状细胞癌(ESCC)是一种常见的恶性肿瘤。小细胞外囊泡中的程序性死亡配体1(sEV-PDL1)可诱导免疫逃避并促进肿瘤进展。然而,ESCC衍生的sEV-PDL1在调节CD8+T细胞方面的作用仍不清楚。用 sEVs 分离、刺激和培养 CD8+T 细胞,通过流式细胞术评估其比例、表型和功能。利用慢病毒感染和 Crisper-Cas9 技术构建了稳定的转基因细胞系:Eca109-PDL1kd和mEC25-PDL1ko。结果显示,ESCC患者的CD8+T细胞比例低于健康供体(HD)。此外,还观察到 sEV-PDL1 与 CD8+T 细胞呈负相关。sEV-PDL1 通过降低 Ki67、颗粒酶 B (GrzmB) 和干扰素-γ (IFN-γ) 在体外和体内的表达水平,诱导 CD8+T 细胞衰竭。然而,抗 PDL1 可逆转这一结果。我们的研究结果表明,靶向 sEV-PDL1 使 CD8+T 细胞功能恢复活力是一种很有前景的 ESCC 治疗策略。
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Esophageal squamous cell carcinoma derived sEV-PDL1 exhausts CD8+T cells to promote immunosuppression
Esophageal squamous cell carcinoma (ESCC) is a common malignancy. Programmed death ligand 1 of small extracellular vesicles (sEV-PDL1) induce immune evasion and enhance tumor progression. However, the role of ESCC derived sEV-PDL1 in modulating CD8+T cell remains unclear. sEVs were isolated through differential centrifugation. CD8+T cells were isolated, stimulated and cultured with sEVs to evaluate the proportions, phenotypes, and functions by flow cytometry. Lentivirus infection and Crisper-Cas9 were used to constructed stable transgenic cell lines: Eca109-PDL1kd and mEC25-PDL1ko. The proportions of CD8+T cells in ESCC patients was lower than healthy donors (HD). Furthermore, a negative correlation between sEV-PDL1 and CD8+T cell was observed. sEV-PDL1 induced CD8+T cell exhaustion by reducing the expression levels of Ki67, Granzyme B (GrzmB), and interferon-γ (IFN-γ) both in vitro and in vivo. However, anti-PDL1 reversed the result. Our findings reveal that targeting sEV-PDL1 to rejuvenate CD8+T cell functions is one of the mechnisms a promising therapeutic strategy for ESCC.
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来源期刊
Molecular immunology
Molecular immunology 医学-免疫学
CiteScore
6.90
自引率
2.80%
发文量
324
审稿时长
50 days
期刊介绍: Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to: Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology Mechanisms of induction, regulation and termination of innate and adaptive immunity Intercellular communication, cooperation and regulation Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc) Mechanisms of action of the cells and molecules of the immune system Structural analysis Development of the immune system Comparative immunology and evolution of the immune system "Omics" studies and bioinformatics Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc) Technical developments.
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