Venetoclax enhances T cell–mediated antileukemic activity by increasing ROS production

• DOI: 10.1182/blood.2020009081
• Publication Date: 2021-03-17T03:55:39Z
• Authors: Jong Bok Lee; Dilshad H. Khan; Rose Hurren; Mingjing Xu; Yoosu Na; Hyeonjeong Kang; Sara Mirali; Xiaoming Wang; Marcela Gronda; Yulia Jitkova; Neil MacLean; Andrea Arruda; Zoe Alaniz; Marina Y. Konopleva; Michael Andreeff; Mark D. Minden; Li Zhang; Aaron D. Schimmer
• Keywords: Venetoclax

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.