白血病仍然是全球死亡率的一个主要原因，对大量癌症患者构成重大健康风险。尽管该领域取得了显着的进步，但现有的治疗方法常常表现出有限的疗效或复发。在这里，我们探索了消除肿瘤中 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）并预防其复发的有效方法的潜力。通过公共数据分析揭示了 HVEM 与白血病之间的临床相关性。利用CRISPR-Cas9技术产生HVEM敲除（KO）小鼠T细胞淋巴细胞白血病细胞系EL4，并建立同基因皮下肿瘤模型以研究HVEM的体内功能。使用免疫组织化学（IHC）、RNA-seq和流式细胞术分析肿瘤免疫微环境（TIME）和肿瘤引流淋巴结（dLN）。通过体内免疫亚群的耗竭和体外 T 细胞功能测定来研究免疫功能。构建HVEM突变型EL4细胞系是为了研究负责免疫逃逸的功能域。根据公共数据库，HVEM在ALL和急性髓系白血病（AML）患者中高表达，并且与患者预后呈负相关。 EL4细胞中HVEM的基因缺失显着抑制了肿瘤进展并延长了荷瘤小鼠的生存期。我们的实验证明HVEM在体内和体外通过CRD1结构域抑制CD8 T细胞的抗肿瘤功能而发挥其免疫抑制作用。此外，我们还发现了一种能够完全根除 ALL 肿瘤的联合疗法，该疗法可诱导针对肿瘤保护的免疫记忆。我们的研究揭示了 HVEM 促进 ALL 进展的潜在机制，并强调 HVEM 作为复发性 ALL 治疗临床应用的一个有前景的靶点。 © 2024。施普林格自然瑞士股份公司。

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.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.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.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.© 2024. Springer Nature Switzerland AG.