2. Academic Validation
  3. CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance

CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance

  • Cell Rep Med. 2023 Jan 13;100917. doi: 10.1016/j.xcrm.2023.100917.
Ling Wu 1,  Joanna Brzostek 1,  Previtha Dawn Sakthi Vale 1,  Qianru Wei 2,  Clara K T Koh 1,  June Xu Hui Ong 1,  Liang-Zhe Wu 1,  Jia Chi Tan 1,  Yen Leong Chua 1,  Jiawei Yap 1,  Yuan Song 3,  Vivian Jia Yi Tan 1,  Triscilla Y Y Tan 2,  Junyun Lai 4,  Paul A MacAry 5,  Nicholas R J Gascoigne 6
Affiliations

Affiliations

  • 1 Immunology 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.
  • 2 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore.
  • 3 Immunology 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.
  • 4 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.
  • 5 Immunology 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.
  • 6 Immunology 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.
PMID: 36696897 DOI: 10.1016/j.xcrm.2023.100917
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.

Keywords

CAR; CAR-T; CD28; FYN; LCK independent signaling; T cell receptor; allogeneic CAR-T; chimeric antigen receptor T cell; co-stimulation; signal transduction; specificity.

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