BACH2 regulates T cell lineage states to overcome dysfunction driven by tonic CAR signaling

作者：Tien-Ching Chang, Amanda Heard, Jake Lattin, Amanda Barrett, Jack H. Landmann, John M. Warrington, Yangdon Tenzin, Sadia Afrin, Deepesh Kumar Gupta, Ju Fang Chang, Julie Ritchey, Mehmet Emrah Selli, Yu-Sung Hsu, Haorui Song, Avery Horn, Evan W. Weber, Tom Wandless, Jeremy Chase Crawford, Paul G. Thomas, John F. DiPersio, Nathan Singh · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-108 · 被引用次数：2 · 研究领域：CAR-T cell therapy research、T-cell and B-cell Immunology、Cancer Immunotherapy and Biomarkers

Abstract Like T cell receptors (TCRs), chimeric antigen receptors (CARs) trigger potent intracellular signaling upon engagement with antigen, a process which initiates cell state transitions that direct T cell functionality. Unlike TCRs, CARs have an intrinsic predisposition to initiate intracellular signaling in the absence of target antigen, referred to as “tonic” signaling. Tonic CAR signaling of CARs containing the CD28 costimulatory domain has previously been shown to be a potent driver of T cell exhaustion. We previously showed that, in contrast to CD28, CARs containing the 41BB costimulatory domain acquire enhanced functionality from tonic signaling. These data indicate that the impact of tonic CAR signaling is directly dependent on the CAR costimulatory domain. To understand the molecular regulators of the enhanced T cell function induced by tonic 41BB signaling, we generated CARs targeting the B cell antigen CD22 that contained either CD28 or 41BB costimulatory domains that did (22/BB-S, 22/28-S) or did not (22/BB-L, 22/28-L) signal tonically. We confirmed that tonic signaling of CD28 impaired T cell function upon coculture with the CD22+ human ALL cell line Nalm6, while tonic 41BB-based CAR signaling enhanced function. RNA sequencing demonstrated 22/BB-S expressed higher memory-associated genes (ie. CCR7, TCF7) and a gene program regulated by BACH2. To investigate if BACH2 is responsible for the enhanced function of 22/BB-S we generated 22/28-S cells that overexpres...