1566 Fate induction through asymmetric T cell division is modulated by chimeric antigen receptor co-stimulatory domains

Chimeric antigen receptor T cell (CART) therapy has been shown to induce complete remissions in hematologic malignancies and lupus. Long-term persistence of CARTs disease remission are established through generation long-lived memory cells. CARs expressing CD137 co-stimulatory domains demonstrate superior compared CD28 co-stimulated CARs, although the mechanism underlying this differential longevity is unknown. We recently that utilize asymmetric division (ATCD) effector fate selection. Here we show specifically modulate ATCD resulting strength differentiation following first after target encounter. Both establish specific surface protein asymmetry proximal daughters (PDs) distal (DD), overlapping but distinct daughter proteomes CARTs. While both divergent transcriptional profiles cells, only induces a signature DD PD, respectively (adjusted p-value < 1e-6). Mechanistically, coordinates robust metabolic reprograming with enhanced glycolysis oxidative phosphorylation PD DD, (p=0.014) whereas fails asymmetrically polarize metabolism.In vivo characterization cells humanized leukemia mouse model confirms as exhibit inferior eradication (n=4-9 per group, p<0.01). In conclusion, for identify novel therapeutic targets promoting CART differentiation.