Cytotoxicity of CD19-CAR-NK92 cells is primarily mediated via perforin/granzyme pathway.
CAR
Chimeric antigen receptor
Death receptor
Granzyme
Lymphoid malignancies
NK92-cells
Perforin
Journal
Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732
Informations de publication
Date de publication:
Aug 2023
Aug 2023
Historique:
received:
13
11
2022
accepted:
28
03
2023
medline:
24
7
2023
pubmed:
14
4
2023
entrez:
13
4
2023
Statut:
ppublish
Résumé
Chimeric antigen receptors (CARs) have improved cancer immunotherapy in recent years. Immune cells, such as Natural killer cells (NK-cells) or T cells, are used as effector cells in CAR-therapy. NK92-cells, a cell line with known cytotoxic activity, are of particular interest in CAR-therapy since culturing conditions are simple and anti-tumor efficacy combined with a manageable safety profile was proven in clinical trials. The major pathways of immune effector cells, including NK92-cells, to mediate cytotoxicity, are the perforin/granzyme and the death-receptor pathway. Detailed knowledge of CAR-effector cells' cytotoxic mechanisms is essential to unravel resistance mechanisms, which potentially arise by resistance against apoptosis-inducing signaling. Since mutations in apoptosis pathways are frequent in lymphoma, the impact on CAR-mediated cytotoxicity is of clinical interest. In this study, knockout models of CD19-CAR-NK92 cells were designed, to investigate cytotoxic pathways in vitro. Knockout of perforin 1 (Prf1) and subsequent abrogation of the perforin/granzyme pathway dramatically reduced the cytotoxicity of CD19-CAR-NK92 cells. In contrast, knockout of FasL and inhibition of TRAIL (tumor necrosis factor-related apoptosis-inducing ligands) did not impair cytotoxicity in most conditions. In conclusion, these results indicate the perforin/granzyme pathway as the major pathway to mediate cytotoxicity in CD19-CAR-NK92 cells.
Identifiants
pubmed: 37052701
doi: 10.1007/s00262-023-03443-1
pii: 10.1007/s00262-023-03443-1
pmc: PMC10361870
doi:
Substances chimiques
Perforin
126465-35-8
Receptors, Chimeric Antigen
0
Granzymes
EC 3.4.21.-
Antigens, CD19
0
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2573-2583Subventions
Organisme : Ruhr University Bochum
ID : F978-2020
Informations de copyright
© 2023. The Author(s).
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