Epigenetic Editing Balances TCR Suppression and Persistence in CAR T cells
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ABSTRACT:
PROVIDER: PRJNA1276116 | ENA |
REPOSITORIES: ENA
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Project description:Insufficient functional T cell persistence impedes therapeutic success of chimeric antigen receptor (“CAR”) therapies. Here, we performed a CAR-adapted base editing screen of PIK3CD, a key regulator of T cell function, metabolism, and fate. We identified point mutations that beneficially modulate CAR T cell profiles in 4-1BBz and 28z CAR T cells, respectively. Remarkably, point mutations with differing effects on PI3Kδ signaling activity were advantageous in distinct CAR contexts: The PI3Kδ-activating mutation E81K enhanced proliferation, metabolic fitness and effector function in 4-1BBz CARs, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo. Conversely, the PI3Kδ-attenuating mutation L32P improved T cell memory formation and functionality in 28z CAR T cells. Together, our approach of Rational Optimization of Activation-dependent Signaling via Targeted Allelic Reprogramming (ROADSTAR) illustrates the importance of CAR design-specific fine-tuning of tailoring intrinsic T cell signaling and demonstrates the potential of base editing for next-generation cellular therapies. Raw data files not provided due to data sensitivity and privacy concerns.
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