Journal
CELL REPORTS
Volume 21, Issue 1, Pages 17-26Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.015
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Funding
- NIH [5P01 CA094237, P50 CA126752, R01 AI067946]
- ASH Scholar Award
- Fundacao para a Ciencia e Tecnologia (FCT, Portugal) [SFRH/BD/52479/2014]
- [NCI P30 CA125123]
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Antigen-independent tonic signaling by chimeric antigen receptors (CARs) can increase differentiation and exhaustion of T cells, limiting their potency. Incorporating 4-1BB costimulation in CARs may enable T cells to resist this functional exhaustion; however, the potential ramifications of tonic 4-1BB signaling in CAR T cells remain unclear. Here, we found that tonic CAR-derived 4-1BB signaling can produce toxicity in T cells via continuous TRAF2-dependent activation of the nuclear factor kappa B (NF kappa B) pathway and augmented FAS-dependent cell death. This mechanism was amplified in a non-selfinactivating 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 T cell 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.
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