Abstract
Antigen-independent tonic signaling by chimeric antigen receptors (CARs) can increase differentiation and exhaustion of Tcells, limiting their potency. Incorporating 4-1BB costimulation in CARs may enable Tcells to resist this functional exhaustion; however, the potential ramifications of tonic 4-1BB signaling in CAR Tcells remain unclear. Here, we found that tonic CAR-derived 4-1BB signaling can produce toxicity in Tcells via continuous TRAF2-dependent activation of the nuclear factor κB (NF-κB) pathway and augmented FAS-dependent cell death. This mechanism was amplified in a non-self-inactivating gammaretroviral vector through positive feedback on the long terminal repeat (LTR) promoter, further enhancing CAR expression and tonic signaling. Attenuating CAR expression by substitution with a self-inactivating lentiviral vector minimized tonic signaling and improved Tcell expansion and anti-tumor function. These studies illuminate the interaction between tonic CAR signaling and the chosen expression platform and identify inhibitory properties of the 4-1BB costimulatory domain that have direct implications for rational CAR design.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have