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

Area of Science:

• Immunology
• Hematology
• Pharmacology

Background:

• Venetoclax plus azacytidine shows high remission rates in acute myeloid leukemia (AML) patients unfit for chemotherapy.
• The precise mechanism of action for this combination therapy remains incompletely understood.

Purpose of the Study:

• To elucidate the immune-mediated mechanisms underlying the efficacy of venetoclax and azacytidine in AML treatment.
• To explore the potential of combining venetoclax with adoptive cell therapy for AML.

Main Methods:

• In vitro and in vivo experiments assessing T-cell activation and cytotoxicity against AML cells.
• Analysis of reactive oxygen species (ROS) generation and STING/cGAS pathway activation.
• Evaluation of T-cell responses in patients undergoing venetoclax treatment.

Main Results:

• Venetoclax directly activates T cells, enhancing their cytotoxicity against AML by increasing ROS generation via inhibition of respiratory chain supercomplexes.
• Azacytidine induces viral mimicry in AML cells by activating the STING/cGAS pathway, increasing susceptibility to T cell-mediated killing.
• Patients treated with venetoclax exhibited increased ROS generation and T-cell activation.

Conclusions:

• This study reveals a novel immune-mediated mechanism for venetoclax and azacytidine in AML treatment.
• The findings support the potential of combining venetoclax with adoptive cell therapy for enhanced AML treatment strategies.