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Transcriptional changes in human natural killer cells derived from umbilical cord blood in response to the BCL-2 inhibitor Venetoclax

ABSTRACT: Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment, but its efficacy is still limited, necessitating the development of new strategies. Here, we report an unexpected discovery that venetoclax, the first FDA-approved BCL-2 inhibitor, acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against acute myeloid leukemia (AML). Venetoclax directly activates human NK cells, boosting their cytotoxicity against AML both in vitro and in vivo, independent of BCL-2 inhibition. Venetoclax enhances NK cell binding avidity and lytic granule polarization during immunological synapse (IS) formation.Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, facilitating IS formation and effector function in human NK cells.Our findings establish venetoclax as a multifaceted immunometabolic modulator that enhances NK cell function, providing new insights for augmenting NK cell-mediated cytotoxicity in cancer immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237922 | GEO | 2023/07/31

REPOSITORIES: GEO

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Single-cell transcriptome analysis of human natural killer cells derived from umbilical cord blood in response to the BCL-2 inhibitor venetoclax

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