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

Ling Wu; Joanna Brzostek; Previtha Dawn Sakthi Vale; Qianru Wei; Clara K.T. Koh; June Xu Hui Ong; Liang zhe Wu; Jia Chi Tan; Yen Leong Chua; Jiawei Yap; Yuan Song; Vivian Jia Yi Tan; Triscilla Y.Y. Tan; Junyun Lai; Paul A. MacAry; Nicholas R.J. Gascoigne

doi:10.1016/j.xcrm.2023.100917

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

Ling Wu, Joanna Brzostek, Previtha Dawn Sakthi Vale, Qianru Wei, Clara K.T. Koh, June Xu Hui Ong, Liang zhe Wu, Jia Chi Tan, Yen Leong Chua, Jiawei Yap, Yuan Song, Vivian Jia Yi Tan, Triscilla Y.Y. Tan, Junyun Lai, Paul A. MacAry, Nicholas R.J. Gascoigne

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English (US)
Article number	100917
Journal	Cell Reports Medicine
Volume	4
Issue number	2
DOIs	https://doi.org/10.1016/j.xcrm.2023.100917
State	Published - Feb 21 2023
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2023.100917

Cite this

Wu, L., Brzostek, J., Sakthi Vale, P. D., Wei, Q., Koh, C. K. T., Ong, J. X. H., Wu, L. Z., Tan, J. C., Chua, Y. L., Yap, J., Song, Y., Tan, V. J. Y., Tan, T. Y. Y., Lai, J., MacAry, P. A., & Gascoigne, N. R. J. (2023). CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance. Cell Reports Medicine, 4(2), Article 100917. https://doi.org/10.1016/j.xcrm.2023.100917

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

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 = "allogeneic CAR-T, CAR, CAR-T, CD28, chimeric antigen receptor T cell, co-stimulation, FYN, LCK independent signaling, signal transduction, specificity, T cell receptor",

author = "Ling Wu and Joanna Brzostek and {Sakthi Vale}, {Previtha Dawn} and Qianru Wei and Koh, {Clara K.T.} and Ong, {June Xu Hui} and Wu, {Liang zhe} and Tan, {Jia Chi} and Chua, {Yen Leong} and Jiawei Yap and Yuan Song and Tan, {Vivian Jia Yi} and Tan, {Triscilla Y.Y.} and Junyun Lai and MacAry, {Paul A.} and Gascoigne, {Nicholas R.J.}",

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year = "2023",

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day = "21",

doi = "10.1016/j.xcrm.2023.100917",

language = "English (US)",

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AU - Wu, Ling

AU - Brzostek, Joanna

AU - Sakthi Vale, Previtha Dawn

AU - Wei, Qianru

AU - Koh, Clara K.T.

AU - Ong, June Xu Hui

AU - Wu, Liang zhe

AU - Tan, Jia Chi

AU - Chua, Yen Leong

AU - Yap, Jiawei

AU - Song, Yuan

AU - Tan, Vivian Jia Yi

AU - Tan, Triscilla Y.Y.

AU - Lai, Junyun

AU - MacAry, Paul A.

AU - Gascoigne, Nicholas R.J.

PY - 2023/2/21

Y1 - 2023/2/21

N2 - 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.

AB - 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.

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KW - chimeric antigen receptor T cell

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KW - LCK independent signaling

KW - signal transduction

KW - specificity

KW - T cell receptor

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

Abstract

Keywords

ASJC Scopus subject areas

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