Targeting Mitochondrial Apoptosis Improves NK cell–Based Immunotherapies

Natural killer (NK) cells are components of the innate immune system that kill malignant cells through use of activating receptors typically upregulated on cancer cells in a process that is major histocompatibility complex–independent. NK-based immunotherapies, including adoptive transfer of allogeneic NK cells, show a low risk of graft-versus-host disease and cytokine release syndrome and have demonstrated promise in preclinical and clinical models. Despite these encouraging results, efficacy of this type of therapy remains limited. Therefore, Pan and colleagues sought to address this issue by determining modes of NK-cell killing of cancer cells, finding that preactivated primary NK cells induce mitochondrial apoptosis (mtApoptosis) of tumor cells from both liquid and solid tumor cell lines. This was evidenced by the loss of mitochondrial outer membrane potential, the rapid release of cytochrome c, and other features of apoptotic cell death. Use of BAX/BAK double-knockout cells, which are mtApoptosis-deficient, showed a significant reduction in NK-mediated cell killing as compared to wild-type cells, with mtApoptosis induction being required for efficient cell killing at effector-to-target ratios lower than 1:1, which are typical in vivo ratios, but less so at higher ones. Use of BH3 profiling to investigate mtApoptosis priming of cancer cells revealed that NK cells increased mitochondrial priming of tumor cells while reducing mitochondrial priming by overexpressing antiapoptotic proteins, such as BCL-2 and MCL-1, consequently reducing cancer cell susceptibility to NK-cell killing. Preactivated NK cells together with BH3 mimetics synergized to both prime and kill cancer cells both in vitro and in vivo in both blood and solid tumor types. Moreover, experiments suggested the use of BH3 mimetics could also synergize with T cell–mediated immunotherapies. In summary, this study reveals that mtApoptosis is needed for NK cell–mediated priming and killing of tumor cells at more physiologically relevant effector-to-target ratios (< 1:1) and suggests the use of BH3 mimetics to provide synergistic benefit to NK-cell therapies.

Pan R, Ryan J, Pan D, Wucherpfennig KW, Letai A. Augmenting NK cell-based immunotherapy by targeting mitochondrial apoptosis. Cell 2022;185:1521–38.e18.

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