BACH2 regulates T cell lineage state to enhance CAR T cell function.

Area of Science:

• Immunology
• Cancer Biology
• Cellular Therapy

Background:

• Chimeric antigen receptors (CARs) often exhibit tonic signaling, influencing T cell function.
• CARs with 41BB domains promote T cell fitness, unlike CD28-containing CARs that induce exhaustion.

Purpose of the Study:

• To investigate the role of the transcriptional regulator BACH2 in CAR T cell function.
• To explore strategies for optimizing CAR T cell efficacy by modulating BACH2 activity.

Main Methods:

• Investigated the effect of 41BB-induced BACH2 on CAR T cell states.
• Overexpressed and degradation-tagged BACH2 in CAR T cells.
• Assessed CAR T cell exhaustion, proliferation, and effector function.
• Analyzed clinical CAR T cell products for BACH2 association with outcomes.

Main Results:

• 41BB signaling induces BACH2, which directs stem and memory programs.
• BACH2 overexpression prevented exhaustion but caused T cell quiescence.
• Tuning BACH2 with a degradation domain prevented exhaustion while maintaining potent effector function.
• Enhanced CAR T cell efficacy against liquid and solid tumors was observed.
• BACH2 activity correlated with clinical outcomes in leukemia patients.

Conclusions:

• BACH2 is a key regulator of CAR T cell efficacy, balancing T cell fitness and function.
• Modulating BACH2 activity represents a promising strategy to enhance CAR T cell therapy for various cancers.