Phosphotyrosine Signal Profiling of Clinical CAR-T Reveals Tonic Signaling Associated with Therapeutic Efficacy

doi:10.1101/2024.12.22.629940

	Phosphotyrosine Signal Profiling of Clinical CAR-T Reveals Tonic Signaling Associated with Therapeutic Efficacy
	Yao, Bin 1,2; Ye, Xueting 1,2,3; Kong, Qian 1,2; Chen, Wendong 1,2; Li, Wentao4 ; Feng, Chun 3; He, An 1,2; Li, Guoqiang 3; Chen, Lan 1,2; Chen, Xiong 1,2; Hu, Lina 3; Xie, Lifen 1,2,3; Qiu, Xiao 3; Wang, Xi 1,2,3; Lin, Yuhong 1,2; Cao, Yixuan 3; Zhou, Jihao 3; Zhang, Xinyou 3; Wang, Haopeng4 ; Tian, Ruijun 1,2
	2024-12-22
状态	已发表
摘要	Chimeric Antigen Receptor T (CAR-T) therapies have revolutionized the treatment of cancers such as relapsed and refractory B cell malignancies. However, the precise therapeutic mechanism of CAR-T action remain to be elucidated. In this study, we systematically analyzed CAR signaling via phosphotyrosine (pTyr) proteomics in CAR-T cells from both clinical patients and healthy donors. We found that CAR-T products from clinical patients displayed heightened tyrosine phosphorylation, particularly in the JAK-STAT, MAPK and TCR signaling cascades. We also identified the significantly regulated pTyr sites in primary CAR-T cells under tonic signaling or upon stimulation by antigen-presenting CD19-K562 cells. Although both CD28{zeta} and 4-1BB{zeta} CAR-T cells exhibited comparable pTyr changes, CD28{zeta} CAR-T cells displayed a more pronounced activation in the TCR signaling pathway. Additionally, comparative analysis between clinical and primary CAR-T cells suggested that CAR-T products were subject to heightened tonic signaling, which may be related to therapeutic relapse. Our findings reveal the state of clinical CAR-T products and refine the CAR-T signal transduction network, providing comprehensive insights and informed guidance for CAR-T therapies.
语种	英语
DOI	10.1101/2024.12.22.629940
相关网址	查看原文
出处	bioRxiv
收录类别	PPRN.PPRN
WOS记录号	PPRN:120090897
WOS类目	Immunology
资助项目	Shenzhen Innovation of Science and Technology Commission["JCYJ20210324120210029","JSGGZD20220822095200001","JCYJ20200109141212325","JCYJ20200109140814408"] ; Guangdong province[2019B151502050]
文献类型	预印本
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/483985
专题	生命科学与技术学院生命科学与技术学院_PI研究组_王皞鹏组生命科学与技术学院_博士生
通讯作者	Zhou, Jihao; Zhang, Xinyou; Wang, Haopeng; Tian, Ruijun
作者单位	1.Southern Univ Sci & Technol, Dept Chem, Shenzhen 518055, Peoples R China 2.Southern Univ Sci & Technol, Coll Sci, Res Ctr Chem Biol & Omics Anal, Shenzhen 518055, Peoples R China 3.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2,Affiliated Hosp 1, Shenzhen 518020, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Yao, Bin,Ye, Xueting,Kong, Qian,et al. Phosphotyrosine Signal Profiling of Clinical CAR-T Reveals Tonic Signaling Associated with Therapeutic Efficacy. 2024.