| Autor: |
Mehmet Emrah Selli, Jack Landmann, Marina Terekhova, John Lattin, Amanda Heard, Yu-Sung Hsu, Tien-Ching Chang, Ju-fang Chang, John M Warrington, Helen Ha, Natalie L Kingston, Graham Hogg, Michael Slade, Melissa M Berrien-Elliott, Mark Foster, Samantha Kersting-Schadek, Agata Gruszczynska, David DeNardo, Todd A Fehniger, Maxim Artyomov, Nathan Singh |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
bioRxiv |
| Popis: |
T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have demonstrated impressive activity against relapsed or refractory B cell cancers yet fail to induce durable remissions for nearly half of patients treated. Enhancing the efficacy of this therapy requires detailed understanding of the molecular circuitry that restrains CAR-driven anti-tumor T cell function. We developed and validated an in vitro model that drives T cell dysfunction through chronic CAR activation and interrogated how CAR costimulatory domains, central components of CAR structure and function, contribute to T cell failure. We found that chronic activation of CD28-based CARs results in activation of classical T cell exhaustion programs and development of dysfunctional cells that bear the hallmarks of exhaustion. In contrast, 41BB-based CARs activate a divergent molecular program and direct differentiation of T cells into a novel cell state. Interrogation of CAR T cells from a patient with progressive lymphoma confirmed activation of this novel program in a failing clinical product. Further, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is directly responsible for impairing CAR T cell function. These findings identify that costimulatory domains are critical regulators of CAR-driven T cell failure and that targeted interventions are required to overcome costimulation-dependent dysfunctional programs. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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