Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-03-18 Epub Date: 2025-02-20 DOI:10.1016/j.xcrm.2025.101977

Haoran Mu, Qi Zhang, Dongqing Zuo, Jinzeng Wang, Yining Tao, Zhen Li, Xin He, Huanliang Meng, Hongsheng Wang, Jiakang Shen, Mengxiong Sun, Yafei Jiang, Weisong Zhao, Jing Han, Mengkai Yang, Zhuoying Wang, Yu Lv, Yuqin Yang, Jing Xu, Tao Zhang, Liu Yang, Jun Lin, Feng Tang, Renhong Tang, Haiyan Hu, Zhengdong Cai, Wei Sun, Yingqi Hua

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引用次数: 0

Abstract

Osteosarcoma (OS), a malignant bone tumor with limited treatment options, exhibits low sensitivity to immune checkpoint therapy (ICT). Through genomics and transcriptomics analyses, we identify a subgroup of OS with methylthioadenosine phosphorylase (MTAP) deletion, which contributes to ICT resistance, leading to a "cold" tumor microenvironment. MTAP-deleted OS relies on methionine metabolism and is sensitive to methionine intervention, achieved through either dietary restriction or inhibition of methionine adenosyltransferase 2a (MAT2A), a key enzyme in methionine metabolism. We further demonstrate that methionine intervention triggers programmed death-ligand 1 (PD-L1) transcription factor IKAROS family zinc finger 1 (IKZF1) and enhances PD-L1 expression in MTAP-deleted OS cells. Methionine intervention also activates the immune-related signaling pathways in MTAP-deleted OS cells and attracts CD8⁺ T cells, thereby enhancing the efficacy of ICT. Combining methionine intervention with ICT provides a significant survival benefit in MTAP-deleted OS murine models, suggesting a rationale for combination regimens in OS ICT.

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蛋氨酸干预诱导PD-L1表达，增强mtap缺失骨肉瘤的免疫检查点治疗反应。

骨肉瘤（OS）是一种治疗方案有限的恶性骨肿瘤，对免疫检查点治疗（ICT）的敏感性较低。通过基因组学和转录组学分析，我们确定了一个具有甲基硫腺苷磷酸化酶（MTAP）缺失的OS亚群，该亚群有助于ICT抗性，导致“冷”肿瘤微环境。mtap缺失的OS依赖于蛋氨酸代谢，对蛋氨酸干预敏感，通过限制饮食或抑制蛋氨酸腺苷转移酶2a （MAT2A）来实现，MAT2A是蛋氨酸代谢的关键酶。我们进一步证明蛋氨酸干预触发程序性死亡配体1 （PD-L1）转录因子IKAROS家族锌指1 (IKZF1)，并增强mtap缺失的OS细胞中PD-L1的表达。蛋氨酸干预还激活mtap缺失OS细胞中的免疫相关信号通路，吸引CD8+ T细胞，从而增强ICT的疗效。在mtap缺失的OS小鼠模型中，将蛋氨酸干预与ICT联合使用可显著提高生存期，这提示了在OS ICT中使用联合方案的基本原理。

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

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.