CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
BACH2 调控 T 细胞谱系状态以增强 CAR-T 细胞功能
英文原题：BACH2 regulates T cell lineage state to enhance CAR T cell function.
查看英文原题
BACH2 regulates T cell lineage state to enhance CAR T cell function.
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中文摘要
几乎所有嵌合抗原受体（CAR）在无抗原时也会传递信号，这种现象称为“基础性信号”。含41BB结构域的CAR所产生的基础性信号可增强T细胞适应性和功能；相比之下，含CD28结构域的CAR会驱动T细胞耗竭。本文显示，41BB可诱导转录调节因子BACH2表达，而BACH2可调控干细胞和记忆细胞程序。BACH2过表达成功阻止了CAR-T 细胞耗竭，但也使细胞停留在静息状态。我们将BACH2与降解结构域融合以调控其水平，从而在避免细胞耗竭的同时保留强效应功能，并广泛提高CAR-T 细胞靶向血液肿瘤和实体瘤的长期疗效。通过分析临床CAR-T 产品，我们还发现BACH2活性与白血病患者的临床结局相关。这些数据揭示BACH2在调节CAR-T 细胞疗效中的核心作用。
展开英文摘要原文
Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as 'tonic signaling'. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the exhaustion driven by CD28-containing CARs.
Here we show that 41BB induces BACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 successfully prevented exhaustion but locked CAR T cells in a quiescent state.
We linked BACH2 to a degradation domain to tune BACH2, enabling us to prevent exhaustion while enabling potent effector function that broadly enhanced the long-term efficacy of CAR T cells targeting liquid and solid tumors. Through interrogation of clinical CAR products, we further found an association between BACH2 activity and clinical outcomes in patients with leukemia. These data identify a central function for BACH2 in regulating CAR T cell efficacy.
论文信息
- 作者
- Chang TC、Heard A、Lattin J、Warrington JM、Barrett A、Landmann JH、Tenzin Y、Ganesh V
- 第一作者单位
- Division of Oncology, Section of Cellular Therapies, Washington University School of Medicine, St Louis, MO, USA.United States
- 通讯作者单位
- Division of Oncology, Section of Cellular Therapies, Washington University School of Medicine, St Louis, MO, USA. nathan.singh@wustl.edu.United States
- 期刊
- Nature immunology2026 Mar
- 原文标识
- PubMed 41545540 · DOI 10.1038/s41590-025-02391-5
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