HVEM in acute lymphocytic leukemia facilitates tumour immune escape by inhibiting CD8⁺ T cell function.

IF 4.9 2区医学 Q2 CELL BIOLOGY

Cellular Oncology Pub Date : 2024-10-01 Epub Date: 2024-05-29 DOI:10.1007/s13402-024-00959-1

Yujia Liu, Lixiang Wang, Yiyi Li, Cheng Zhong, Xiumei Wang, Xinyu Wang, Zijin Xia, Jing Liao, Chunliu Huang, Chengzhou Mao, Yongyi Feng, Congzhou Luo, Wenhao Mai, Hongrui Song, Hongyu Li, Lin Bao, Danchun Chen, Yue Sheng, Hui Zhang, Xiaolei Wei, Jun Chen, Wei Yi

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引用次数: 0

Abstract

Purpose: Leukaemia remains a major contributor to global mortality, representing a significant health risk for a substantial number of cancer patients. Despite notable advancements in the field, existing treatments frequently exhibit limited efficacy or recurrence. Here, we explored the potential of abolishing HVEM (herpes virus entry mediator, TNFRSF14) expression in tumours as an effective approach to treat acute lymphoblastic leukaemia (ALL) and prevent its recurrence.

Methods: The clinical correlations between HVEM and leukaemia were revealed by public data analysis. HVEM knockout (KO) murine T cell lymphoblastic leukaemia cell line EL4 were generated using CRISPR-Cas9 technology, and syngeneic subcutaneous tumour models were established to investigate the in vivo function of HVEM. Immunohistochemistry (IHC), RNA-seq and flow cytometry were used to analyse the tumour immune microenvironment (TIME) and tumour draining lymph nodes (dLNs). Immune functions were investigated by depletion of immune subsets in vivo and T cell functional assays in vitro. The HVEM mutant EL4 cell lines were constructed to investigate the functional domain responsible for immune escape.

Results: According to public databases, HVEM is highly expressed in patients with ALL and acute myeloid leukemia (AML) and is negatively correlated with patient prognosis. Genetic deletion of HVEM in EL4 cells markedly inhibited tumour progression and prolonged the survival of tumour-bearing mice. Our experiments proved that HVEM exerted its immunosuppressive effect by inhibiting antitumour function of CD8⁺ T cell through CRD1 domain both in vivo and in vitro. Additionally, we identified a combination therapy capable of completely eradicating ALL tumours, which induces immune memory toward tumour protection.

Conclusions: Our study reveals the potential mechanisms by which HVEM facilitates ALL progression, and highlights HVEM as a promising target for clinical applications in relapsed ALL therapy.

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急性淋巴细胞白血病中的 HVEM 可通过抑制 CD8+ T 细胞功能促进肿瘤免疫逃逸。

目的：白血病仍然是造成全球死亡的一个主要因素，对大量癌症患者的健康构成重大威胁。尽管该领域取得了显著进展，但现有治疗方法经常显示出有限的疗效或复发。在此，我们探讨了取消肿瘤中HVEM（疱疹病毒进入介质，TNFRSF14）表达作为治疗急性淋巴细胞白血病（ALL）和防止其复发的有效方法的潜力：方法：通过公开数据分析揭示了HVEM与白血病之间的临床相关性。利用CRISPR-Cas9技术产生HVEM基因敲除（KO）小鼠T细胞淋巴母细胞白血病细胞株EL4，并建立合成皮下肿瘤模型以研究HVEM的体内功能。免疫组织化学（IHC）、RNA-seq和流式细胞术用于分析肿瘤免疫微环境（TIME）和肿瘤引流淋巴结（dLNs）。通过体内免疫亚群耗竭和体外T细胞功能测试研究了免疫功能。构建了HVEM突变体EL4细胞系，以研究导致免疫逃逸的功能域：公共数据库显示，HVEM在ALL和急性髓性白血病（AML）患者中高表达，并与患者预后呈负相关。在EL4细胞中遗传性删除HVEM可明显抑制肿瘤的发展，并延长肿瘤小鼠的生存期。我们的实验证明，HVEM通过CRD1结构域在体内和体外抑制CD8+ T细胞的抗肿瘤功能，从而发挥免疫抑制作用。此外，我们还发现了一种能够彻底根除 ALL 肿瘤的联合疗法，它能诱导肿瘤保护免疫记忆：我们的研究揭示了HVEM促进ALL进展的潜在机制，并强调了HVEM是复发ALL治疗临床应用的一个有希望的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular Oncology ONCOLOGY-CELL BIOLOGY

CiteScore

10.30

自引率

1.50%

发文量

审稿时长

12 months

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.