Harrer, Dennis Christoph and Bezler, Valerie and Hartley, Jordan and Herr, Wolfgang and Abken, Hinrich (2023) IRF4 downregulation improves sensitivity and endurance of CAR T cell functional capacities. FRONTIERS IN IMMUNOLOGY, 14: 1185618. ISSN 1664-3224,
Full text not available from this repository. (Request a copy)Abstract
Chimeric antigen receptor (CAR) modified T cells can induce complete remissions in patients with advanced hematological malignancies. Nevertheless, the efficacy is mostly transient and remains so far poor in the treatment of solid tumors. Crucial barriers to long-term CAR T cell success encompass loss of functional capacities known as "exhaustion", among others. To extend CAR T cell functionality, we reduced interferon regulatory factor 4 (IRF4) levels in CAR T cells using a one-vector system encoding a specific short-hairpin (sh) RNA along with constitutive CAR expression. At baseline, CAR T cells with downregulated IRF4 showed equal cytotoxicity and cytokine release compared to conventional CAR T cells. However, under conditions of repetitive antigen encounter, IRF4(low) CAR T cells displayed enhanced functionality with superior cancer cell control in the long-term compared with conventional CAR T cells. Mechanistically, the downregulation of IRF4 in CAR T cells resulted in prolonged functional capacities and upregulation of CD27. Moreover, IRF4(low) CAR T cells were more sensitive to cancer cells with low levels of target antigen. Overall, IRF4 downregulation capacitates CAR T cells to recognize and respond to target cells with improved sensitivity and endurance.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RECEPTOR; ANTIGEN; EXPANSION; COSTIMULATION; EXHAUSTION; TARGETS; CAR; IRF4; exhaustion; sensitivity; tumor |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Mar 2024 11:43 |
| Last Modified: | 09 Mar 2024 11:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/59315 |
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