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Amplifying antigen-induced cellular responses with proximity labelling
Shuojun Li1, Yinghui Men1,2, Zihan Wang1
1Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Key Laboratory of RNA Innovation Science and Engineering, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Abstract:
Antigen-induced clustering of cell surface receptors, including T cell receptors and Fc receptors, represents a widespread mechanism in cell signalling activation1,2. However, most naturally occurring antigens, such as tumour-associated antigens, stimulate limited receptor clustering and on-target responses owing to insufficient density3-5. Here we repurpose proximity labelling6, a method used to biotinylate and identify spatially proximal proteins, to amplify designed probes as synthetic antigen clusters on the cell surface. We develop an in vivo proximity-labelling technology controlled by either red light or ultrasound to covalently tag fluorescein probes at high density near a target antigen. Using T cell receptors as an example, we demonstrate that the amplified fluorescein effectively clusters and directs a fluorescein-binding bispecific T cell engager to induce enhanced T cell activation and cytotoxicity. Noninvasive, tissue-selective labelling in multiple syngeneic mouse tumour models produces potent immune responses that rapidly eradicate treated tumours. Efficient cell lysis further promotes epitope spreading to induce systemic immunity against untreated distal lesions and immune memory against rechallenge. Thus, proximity-labelling chemistry holds promise as a generalized strategy to manipulate antigen-dependent receptor function and cell states.
Insights
Researchers developed a novel proximity-labeling technology to amplify synthetic antigen clusters on cell surfaces. This method enhances T-cell activation and triggers potent anti-tumor immune responses, leading to tumor eradication and long-term immunity.
Area of Science:
- Immunology
- Biochemistry
- Molecular Biology
Background:
- Antigen-induced receptor clustering is crucial for cell signaling but often limited by low antigen density.
- Naturally occurring antigens, like tumor-associated antigens, may not induce sufficient receptor clustering for robust immune responses.
Purpose of the Study:
- To develop a proximity-labeling technology for amplifying synthetic antigen clusters on cell surfaces.
- To enhance T-cell receptor (TCR) clustering and downstream signaling for improved anti-tumor immunity.
Main Methods:
- Repurposed proximity labeling to create high-density fluorescein probe clusters near target antigens.
- Developed in vivo proximity-labeling controlled by red light or ultrasound.
- Utilized fluorescein-binding bispecific T-cell engagers to activate T-cells.
Main Results:
- Amplified fluorescein clusters effectively engaged TCRs, enhancing T-cell activation and cytotoxicity.
- Noninvasive, tissue-selective labeling in mouse tumor models led to rapid tumor eradication.
- Induced epitope spreading, promoting systemic immunity and immunological memory.
Conclusions:
- Proximity-labeling chemistry offers a versatile strategy to enhance antigen-dependent receptor function.
- This approach can be generalized to manipulate cell states and immune responses.
- The technology shows promise for cancer immunotherapy by amplifying immune cell activation against tumors.
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