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The 4-1BBζ costimulatory domain in chimeric antigen receptors enhances CD8+ T-cell functionality following T-cell receptor stimulation.
- Source :
- Cancer Cell International; 12/18/2023, Vol. 23 Issue 1, p1-18, 18p
- Publication Year :
- 2023
-
Abstract
- Background: Chimeric antigen receptor (CAR) T-cells have revolutionized the treatment of CD19- and B-cell maturation antigen-positive haematological malignancies. However, the effect of a CAR construct on the function of T-cells stimulated via their endogenous T-cell receptors (TCRs) has yet to be comprehensively investigated. Methods: Experiments were performed to systematically assess TCR signalling and function in CAR T-cells using anti-mesothelin human CAR T-cells as a model system. CAR T-cells expressing the CD28 or 4-1BB costimulatory endodomains were manufactured and compared to both untransduced T-cells and CAR T-cells with a non-functional endodomain. These cell products were treated with staphylococcal enterotoxin B to stimulate the TCR, and in vitro functional assays were performed by flow cytometry. Results: Increased proliferation, CD69 expression and IFNγ production were identified in CD8+ 4-1BBζ CAR T-cells compared to control untransduced CD8+ T-cells. These functional differences were associated with higher levels of phosphorylated ZAP70 after stimulation. In addition, these functional differences were associated with a differing immunophenotype, with a more than two-fold increase in central memory cells in CD8+ 4-1BBζ CAR T-cell products. Conclusion: Our data indicate that the 4-1BBζ CAR enhances CD8+ TCR-mediated function. This could be beneficial if the TCR targets epitopes on malignant tissues or infectious agents, but detrimental if the TCR targets autoantigens. [ABSTRACT FROM AUTHOR]
- Subjects :
- CHIMERIC antigen receptors
CD8 antigen
T cells
B cells
AUTOANTIGENS
Subjects
Details
- Language :
- English
- ISSN :
- 14752867
- Volume :
- 23
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Cancer Cell International
- Publication Type :
- Academic Journal
- Accession number :
- 174268547
- Full Text :
- https://doi.org/10.1186/s12935-023-03171-7