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Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.

ABSTRACT: Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in ∼70% 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.

SUBMITTER: Lee JB

PROVIDER: S-EPMC8310428 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.

Lee Jong Bok JB Khan Dilshad H DH Hurren Rose R Xu Mingjing M Na Yoosu Y Kang Hyeonjeong H Mirali Sara S Wang Xiaoming X Gronda Marcela M Jitkova Yulia Y MacLean Neil N Arruda Andrea A Alaniz Zoe Z Konopleva Marina Y MY Andreeff Michael M Minden Mark D MD Zhang Li L Schimmer Aaron D AD

Blood 20210701 3

Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in ∼70% 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 eff ...[more]

PMID: 34292323

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Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.

Publications

Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.

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