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
基于文库的单细胞 CAR 信号分析揭示了体内持久性的驱动因素
英文原题：Library-based single-cell analysis of CAR signaling reveals drivers of in vivo persistence.
查看英文原题
Library-based single-cell analysis of CAR signaling reveals drivers of in vivo persistence.
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中文摘要
表达嵌合抗原受体（CAR）的工程化 T 细胞的抗肿瘤功能依赖于通过胞内信号结构域（ICD）转导的信号。已知不同的 ICD 驱动不同的表型，但缺乏对 ICD 结构如何指导 T 细胞功能——尤其是在分子层面——的系统性研究。在此，我们使用单细胞测序将多样的信号输入映射到转录输出，聚焦于一个明确的临床相关 ICD 结构文库。基于这些观察，我们在各种背景下对转录上不同的 ICD 变体进行功能表征，以构建从 ICD 组成到表型输出的全面图谱。我们鉴定出一种与一部分 ICD 结构相关的独特强直信号特征，该特征在液体肿瘤中驱动持久的体内持久性和疗效，但在实体肿瘤中则不然。我们的发现致力于解码 CAR 信号设计原则，对合理设计针对体内功能优化的下一代 ICD 结构具有重要意义。
展开英文摘要原文
The anti-tumor function of engineered T cells expressing chimeric antigen receptors (CARs) is dependent on signals transduced through intracellular signaling domains (ICDs). Different ICDs are known to drive distinct phenotypes, but systematic investigations into how ICD architectures direct T cell function-particularly at the molecular level-are lacking.
Here, we use single-cell sequencing to map diverse signaling inputs to transcriptional outputs, focusing on a defined library of clinically relevant ICD architectures. Informed by these observations, we functionally characterize transcriptionally distinct ICD variants across various contexts to build comprehensive maps from ICD composition to phenotypic output.
We identify a unique tonic signaling signature associated with a subset of ICD architectures that drives durable in vivo persistence and efficacy in liquid, but not solid, tumors.
Our findings work toward decoding CAR signaling design principles, with implications for the rational design of next-generation ICD architectures optimized for in vivo function.
论文信息
- 作者
- Perez CR、Garmilla A、Nilsson A、Baghdassarian HM、Gordon KS、Lima LG、Smith BE、Maus MV
- 第一作者单位
- Koch Institute for Integrative Cancer Research, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Singapore-MIT Alliance for Research and Technology Centre, Singapore, Singapore.United States
- 通讯作者单位
- Koch Institute for Integrative Cancer Research, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Singapore-MIT Alliance for Research and Technology Centre, Singapore, Singapore; Ragon Institute of MIT, MGH and Harvard, Cambridge, MA, USA. Electronic address: mbirnb@mit.edu.United States
- 文献类型
- 非美国政府资助研究 · 美国 NIH 资助研究
- 期刊
- Cell systems2025 May 21
- 原文标识
- PubMed 40215972 · DOI 10.1016/j.cels.2025.101260
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