ArticleCell reports. Medicine2023
CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance.
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Article in Cell reports. Medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29citing papers in PubMed
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29 citing papers in PubMed, 36 citations in OpenAlex.
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- Uncovering the molecular basis of kinase activity and substrate recognition with phospho-PCA.bioRxiv : the preprint server for biology · 2025Article
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- Liquid biopsy using plasma proteomics in predicting efficacy and tolerance of PD-1/PD-L1 blockades in NSCLC: a prospective exploratory study.Molecular biomedicine · 2025Article
- IFN-γ-resistant CD28 CAR T cells demonstrate increased survival, efficacy, and durability in multiple murine tumor models.Science translational medicine · 2025Article
- MARC, a novel modular chimeric antigen receptor, improves T cell-based cancer immunotherapies by preventing early T cell exhaustion and enhancing persistence.Journal for immunotherapy of cancer · 2025Article
- Turning "trashed" genomic loci into treasurable sites for integrating chimeric antigen receptors in T and NK cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Silibinin's role in counteracting neuronal apoptosis and synaptic dysfunction in Alzheimer's disease models.Apoptosis : an international journal on programmed cell death · 2025Article
- From TCR fundamental research to innovative chimeric antigen receptor design.Nature reviews. Immunology · 2025Review
- Novel FRET-based Immunological Synapse Biosensor for the Prediction of Chimeric Antigen Receptor-T Cell Function.Small methods · 2025Article
- UNC119 regulates T-cell receptor signalling in primary T cells and T acute lymphocytic leukaemia.Life science alliance · 2025Article
- The TCR and LCK: foundations for T-cell activation and therapeutic innovation.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
16 authors at 1 institution in 1 country.
Ling WuImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Joanna BrzostekImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Previtha Dawn Sakthi ValeImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Qianru WeiDepartment of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Clara K T KohImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
June Xu Hui OngImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Liang-Zhe WuImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Jia Chi TanImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Yen Leong ChuaImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Jiawei YapImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Yuan SongImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
Vivian Jia Yi TanImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Triscilla Y Y TanDepartment of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
Junyun LaiDepartment of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
Paul A MacAryImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore; Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Nicholas R J GascoigneImmunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Electronic address: micnrjg@nus.edu.sg.
National University of Singapore · SG
Funding
No grant is acknowledged in the PubMed record.
Abstract
Signal transduction induced by chimeric antigen receptors (CARs) is generally believed to rely on the activity of the SRC family kinase (SFK) LCK, as is the case with T cell receptor (TCR) signaling. Here, we show that CAR signaling occurs in the absence of LCK. This LCK-independent signaling requires the related SFK FYN and a CD28 intracellular domain within the CAR. LCK-deficient CAR-T cells are strongly signaled through CAR and have better in vivo efficacy with reduced exhaustion phenotype and enhanced induction of memory and proliferation. These distinctions can be attributed to the fact that FYN signaling tends to promote proliferation and survival, whereas LCK signaling promotes strong signaling that tends to lead to exhaustion. This non-canonical signaling of CAR-T cells provides insight into the initiation of both TCR and CAR signaling and has important clinical implications for improvement of CAR function.
Indexed as
Receptors, Chimeric AntigenCD28 AntigensLymphocyte Specific Protein Tyrosine Kinase p56(lck)Proto-Oncogene ProteinsProto-Oncogene Proteins c-fynReceptors, Antigen, T-CellSignal TransductionT-LymphocytesCD28 AntigensLymphocyte Specific Protein Tyrosine Kinase p56(lck)Proto-Oncogene ProteinsProto-Oncogene Proteins c-fynReceptors, Antigen, T-CellReceptors, Chimeric Antigenallogeneic CAR-TCARCAR-TCD28chimeric antigen receptor T cellco-stimulationFYNLCK independent signalingsignal transductionspecificityT cell receptor
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