Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.
Blood
; 138(3): 234-245, 2021 07 22.
Article
en En
| MEDLINE
| ID: mdl-34292323
ABSTRACT
Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in â¼70% of treatment-naive elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that venetoclax directly activated T cells to increase their cytotoxicity against acute myeloid leukemia (AML) in vitro and in vivo. Venetoclax enhanced T-cell effector function by increasing reactive oxygen species generation through inhibition of respiratory chain supercomplexes formation. In addition, azacytidine induced a viral mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T cell-mediated cytotoxicity. Similar findings were seen in patients treated with venetoclax, as this treatment increased reactive oxygen species generation and activated T cells. Collectively, this study presents a new immune-mediated mechanism of action for venetoclax and azacytidine in the treatment of AML and highlights a potential combination of venetoclax and adoptive cell therapy for patients with AML.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Sulfonamidas
/
Linfocitos T
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Leucemia Mieloide Aguda
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Compuestos Bicíclicos Heterocíclicos con Puentes
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Antineoplásicos
Límite:
Adult
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Humans
Idioma:
En
Revista:
Blood
Año:
2021
Tipo del documento:
Article