BACH2 regulates T cell lineage states to overcome dysfunction driven by tonic CAR signaling
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Nearly all chimeric antigen receptors (CARs) initiate intracellular signaling in the absence of antigen, referred to as “tonic signaling”. Tonic signaling of CARs containing the CD28 costimulatory domain has been shown to drive T cell exhaustion; in contrast, we previously found that tonic signaling of 41BB-containing CARs enhances T cell function. Using a panel of CARs targeting the B cell antigen CD22, we identified that tonic 41BB signaling activates BACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 prevented exhaustion but locked CAR T cells in less functional memory states. To overcome this, we linked transgenic BACH2 to a degradation domain, enabling dynamic control of BACH2, and found that tuning BACH2 expression enhanced long-term efficacy of exhaustion-prone CAR T cells targeting liquid and solid tumors. Through interrogation of manufactured CAR products, we also found an association between BACH2 activity and clinical outcomes in patients with leukemia.
