Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent
| Autor: | Joaquim M. S. Cabral, Malcolm K. Brenner, Malini Mukherjee, Jordan S. Orange, Cliona M. Rooney, Giedre Krenciute, Diogo Gomes-Silva, Olga Dakhova, Yueting Zheng, Maksim Mamonkin, Madhuwanti Srinivasan |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Programmed cell death adoptive T cell therapy Cell Survival T-Lymphocytes T cell Genetic Vectors Mutant Chimeric Proteins Receptors Antigen T-Cell T cells Biology Inhibitory postsynaptic potential Article General Biochemistry Genetics and Molecular Biology 4-1BB Tonic (physiology) Viral vector Mice Tumor Necrosis Factor Receptor Superfamily Member 9 03 medical and health sciences Antigens Neoplasm Mice Inbred NOD medicine Animals Humans Leukemia-Lymphoma Adult T-Cell fas Receptor lcsh:QH301-705.5 Positive feedback Cell Death chimeric antigen receptor Gene Expression Regulation Leukemic Lentivirus NF-kappa B Long terminal repeat Chimeric antigen receptor Cell biology 4-1BB Ligand 030104 developmental biology medicine.anatomical_structure costimulation lcsh:Biology (General) Immunology Gammaretrovirus human activities Neoplasm Transplantation Signal Transduction |
| Zdroj: | Cell Reports, Vol 21, Iss 1, Pp 17-26 (2017) |
| ISSN: | 2211-1247 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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