Venetoclax acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against leukemia.

Publisher: Cell Press Country of Publication: United States NLM ID: 101766894 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2666-3791 (Electronic) Linking ISSN: 26663791 NLM ISO Abbreviation: Cell Rep Med Subsets: MEDLINE

Original Publication: [Cambridge, MA] : Cell Press, [2020]-

Bridged Bicyclo Compounds, Heterocyclic*/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic*/therapeutic use ; Killer Cells, Natural*/immunology ; Killer Cells, Natural*/drug effects ; Sulfonamides*/pharmacology ; Leukemia, Myeloid, Acute*/therapy ; Leukemia, Myeloid, Acute*/immunology ; Leukemia, Myeloid, Acute*/pathology ; Immunotherapy, Adoptive*/methods; Humans ; Animals ; Mice ; Cell Line, Tumor ; NF-kappa B/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Mice, Inbred NOD

Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment; however, its efficacy remains limited, necessitating the development of alternative strategies. Here, we report that venetoclax, an FDA-approved BCL-2 inhibitor, directly activates NK cells, enhancing their cytotoxicity against acute myeloid leukemia (AML) both in vitro and in vivo, likely independent of BCL-2 inhibition. Through comprehensive approaches, including bulk and single-cell RNA sequencing, avidity measurement, and functional assays, we demonstrate that venetoclax increases the avidity of NK cells to AML cells and promotes lytic granule polarization during immunological synapse (IS) formation. Notably, we identify a distinct CD161 ^low CD218b ⁺ NK cell subpopulation that exhibits remarkable sensitivity to venetoclax treatment. Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, thereby facilitating IS formation in NK cells. Collectively, our findings establish venetoclax as a multifaceted immunometabolic modulator of NK cell function and provide a promising strategy for augmenting NK cell-based cancer immunotherapy.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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Keywords: NF-κB; RNA sequencing; acute myeloid leukemia; avidity; cytotoxicity; immunological synapse; immunotherapy; mitochondrial respiration; natural killer cells; venetoclax

N54AIC43PW (venetoclax)
0 (Bridged Bicyclo Compounds, Heterocyclic)
0 (Sulfonamides)
0 (NF-kappa B)
0 (Antineoplastic Agents)

Date Created: 20240522 Date Completed: 20240619 Latest Revision: 20240710

20240710

PMC11228450

10.1016/j.xcrm.2024.101580

38776913