Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent

Diogo Gomes-Silva, Malini Mukherjee, Madhuwanti Srinivasan, Giedre Krenciute, Olga Dakhova, Yueting Zheng, Joaquim M.S. Cabral, Cliona M. Rooney, Jordan S. Orange, Malcolm Brenner, Maksim Mamonkin

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

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 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 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. Gomes-Silva et al. model tonic signaling from chimeric antigen receptors (CARs) harboring the 4-1BB endodomain and describe a mechanism through which this signaling produces toxicity in T cells. CAR-driven tonic 4-1BB signaling activates the LTR promoter in gammaretroviral vectors, thus further amplifying the toxicity and undermining CAR T cell anti-tumor activity.

Original languageEnglish (US)
Pages (from-to)17-26
Number of pages10
JournalCell Reports
Volume21
Issue number1
DOIs
StatePublished - Oct 3 2017

Keywords

  • 4-1BB
  • T cells
  • adoptive T cell therapy
  • chimeric antigen receptor
  • costimulation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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