工程化益生菌用于肿瘤靶向联合化学免疫治疗
Engineered probiotics for tumor-targeted combination chemoimmunotherapy.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
短暂羟基胆固醇处理抑制 TCR 信号以促进长期免疫
英文原题：Transient hydroxycholesterol treatment restrains TCR signaling to promote long-term immunity.
查看英文原题
Transient hydroxycholesterol treatment restrains TCR signaling to promote long-term immunity.
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中文摘要
T 细胞受体（TCR）在适应性免疫中发挥基础作用，TCR-T 细胞疗法治疗实体瘤和其他疾病颇具前景，但目前缺乏调节 TCR 活性的化学工具。本研究筛选了天然甾醇对 T 细胞功能的调节作用，发现 7α-羟基胆固醇（7α-HC）是 TCR 信号的强效抑制剂。机制上，7α-HC 改变细胞膜理化性质，促进 CD3 胞质结构域与膜结合；CD3 是 TCR-CD3 复合体的关键信号组成部分。CD3 膜结合增强会妨碍 CD3 与关键激酶 Lck 凝聚，从而抑制 Lck 介导的 TCR 磷酸化。对 TCR-T 进行短暂 7α-HC 处理，可降低信号强度、增加记忆细胞群并增强长期抗肿瘤功能。本研究揭示一种化学调节 TCR 信号的方法，可用于提高 TCR-T 细胞疗法的长期疗效。
展开英文摘要原文
T cell receptor (TCR) plays a fundamental role in adaptive immunity, and TCR-T cell therapy holds great promise for treating solid tumors and other diseases.
However, there is a noticeable absence of chemical tools tuning TCR activity. In our study, we screened natural sterols for their regulatory effects on T cell function and identified 7-alpha-hydroxycholesterol (7a-HC) as a potent inhibitor of TCR signaling.
Mechanistically, 7a-HC promoted membrane binding of CD3 cytoplasmic domain, a crucial signaling component of the TCR-CD3 complex, through alterations in membrane physicochemical properties. Enhanced CD3 membrane binding impeded the condensation between CD3 and the key kinase Lck, thereby inhibiting Lck-mediated TCR phosphorylation. Transient treatments of TCR-T cells with 7a-HC resulted in reduced signaling strength, increased memory cell populations, and superior long-term antitumor functions.
This study unveils a chemical regulation of TCR signaling, which can be exploited to enhance the long-term efficacy of TCR-T cell therapy.
论文信息
- 作者
- Ren Z、Wang K、Zhang Y、Chen H、Zhu Y、Li H、Lou J、Wang H
- 第一作者单位
- Key Laboratory of Multi-Cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.China
- 通讯作者单位
- Key Laboratory of Multi-Cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: cqxu@sibcb.ac.cn.China
- 期刊
- Cell chemical biology2024 May 16
- 原文标识
- PubMed 38759618 · DOI 10.1016/j.chembiol.2024.04.005