1069 Fate induction in CD8 chimeric antigen receptor T cells through asymmetric cell division

Chimeric antigen receptor T-cell (CART) therapy has led to lasting remissions in hematologic cancers and autoimmune diseases including systemic lupus. Long-lived memory CARTs predict clinical response, but mechanisms for CART differentiation after activation remain unclear. Here, we use a novel proximity-labeling method isolate first-division proximal distal daughter cells show that activated human undergo asymmetric T cell division (ATCD) impose distinct fates between cells. Proximal inherit surface proteome similar activated-undivided CARTs; upregulate core transcription factor set promoting proliferation (E2F7), apoptosis (TP73), effector (YBX1); demonstrate glycolytic-predominant metabolic profile consistent with terminal fate. In contrast, exhibit resembling resting quiescence (STAT1) restraining expansion (FLI1); employ an oxidative phosphorylation-predominant profile. RNA velocity analysis reveals transcriptional asymmetry is established by both uneven distribution of pre-existing transcripts changes regulation. Consistent fate, superior engraftment capability compared (p < 0.05). Surprisingly, daughters also transient effector-like cytotoxic potency, resulting long-term leukemic control 0.01). These studies establish ATCD as mechanism provide framework identifying actionable targets towards the optimization immunotherapies.