The 4-1BBζ costimulatory domain in chimeric antigen receptors enhances CD8+ T-cell functionality following T-cell receptor stimulation.

Autor: Chu GJ; Gene and Stem Cell Therapy Program Centenary Institute, Camperdown, NSW, Australia.; Department of Clinical Immunology and Allergy, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia., Bailey CG; Gene and Stem Cell Therapy Program Centenary Institute, Camperdown, NSW, Australia.; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.; Cancer & Gene Regulation Laboratory Centenary Institute, Camperdown, NSW, Australia., Nagarajah R; Gene and Stem Cell Therapy Program Centenary Institute, Camperdown, NSW, Australia., Sagnella SM; Cell & Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, NSW, Australia., Adelstein S; Department of Clinical Immunology and Allergy, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia., Rasko JEJ; Gene and Stem Cell Therapy Program Centenary Institute, Camperdown, NSW, Australia. j.rasko@centenary.org.au.; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia. j.rasko@centenary.org.au.; Cell & Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. j.rasko@centenary.org.au.
Jazyk: angličtina
Zdroj: Cancer cell international [Cancer Cell Int] 2023 Dec 18; Vol. 23 (1), pp. 327. Date of Electronic Publication: 2023 Dec 18.
DOI: 10.1186/s12935-023-03171-7
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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