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Updated: Jun 26, 2025
Generation of Human Chimeric Antigen Receptor Regulatory T Cells
Published on: January 3, 2025
Transient hydroxycholesterol treatment restrains TCR signaling to promote long-term immunity
Zhengxu Ren1, Kun Wang2, Yong Zhang3
1Key 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.
Abstract:
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 CD3ε cytoplasmic domain, a crucial signaling component of the TCR-CD3 complex, through alterations in membrane physicochemical properties. Enhanced CD3ε membrane binding impeded the condensation between CD3ε 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.
Insights
Researchers discovered 7-alpha-hydroxycholesterol (7a-HC) as a chemical tool to inhibit T cell receptor (TCR) signaling. This discovery enhances long-term antitumor functions in TCR-T cell therapy.
Area of Science:
- Immunology
- Cell Signaling
- Chemical Biology
Background:
- T cell receptor (TCR) is crucial for adaptive immunity and TCR-T cell therapy shows promise for cancer treatment.
- A lack of chemical tools to modulate TCR activity limits therapeutic potential.
Purpose of the Study:
- To screen natural sterols for compounds that regulate T cell function.
- To identify and characterize chemical modulators of TCR signaling for improved T cell-based therapies.
Main Methods:
- Screening of natural sterols to identify regulators of T cell function.
- Investigating the mechanism of action of identified compounds on TCR signaling components.
- Assessing the impact of transient treatment with the identified compound on TCR-T cell function and antitumor activity in vitro and in vivo.
Main Results:
- 7-alpha-hydroxycholesterol (7a-HC) was identified as a potent inhibitor of TCR signaling.
- 7a-HC enhances CD3ε membrane binding, disrupting CD3ε-Lck complex formation and inhibiting TCR phosphorylation.
- Transient 7a-HC treatment of TCR-T cells reduced signaling strength, increased memory cell populations, and improved long-term antitumor efficacy.
Conclusions:
- This study reveals a novel chemical regulation of TCR signaling by 7a-HC.
- The findings provide a new strategy to enhance the long-term efficacy of TCR-T cell therapy by modulating TCR signaling strength and promoting memory cell formation.
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