IL-12/15/18-induced cell death and mitochondrial dynamics of human NK cells

Terrén, Íñigo; Sandá, Víctor; Amarilla-Irusta, Ainhoa; Lopez-Pardo, Ainara; Sevilla, Arrate; Astarloa-Pando, Gabirel; Amo, Laura; Zenarruzabeitia, Olatz; Scorrano, Luca; Borrego, Francisco

doi:10.3389/fimmu.2023.1211839

Cited by 8 publications

(3 citation statements)

References 27 publications

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“…In support of this, Terren et al demonstrated that CIML activation of NK cells resulted in decreased viability, likely due in part to failed mitochondrial dynamics and mitophagy. Apoptosis resulting from activation was further confirmed with accumulation of super-oxide and release of cytochrome c in NK cells (59). T cells, particularly CD8+ T cells, undergo AICD as a form of peripheral immune regulation with signaling through Fas/FasL or TNFR2, which is particularly important for the prevention of autoimmune disease (60, 61).…”

Section: Discussionmentioning

confidence: 90%

Replication stress in activated human NK cells induces sensitivity to apoptosis

Guilz,

Ahn,

Fatima

et al. 2023

Preprint

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Natural killer cells are innate immune effectors that kill virally infected or malignant cells. Natural killer cell deficiency (NKD) occurs when NK cell development or function are impaired, and individuals with NKD are susceptible to severe and recurrent viral infections. Several gene deficiencies result in NKD, including variants in MCM4, GINS1, MCM10 and GINS4, which are components of the CDC45-MCM-GINS (CMG) helicase. The CMG helicase unwinds DNA during replication and is expressed in any actively proliferating cell. NK cells are more strongly impacted by mutational deficiencies in helicase proteins than other lymphocytes, though the mechanisms underlying this susceptibility are not completely understood. NK cells from individuals with NKD as a result of helicase deficiency have increased DNA damage, cell cycle arrest, and replication stress. Here, we induced replication stress in activated mature NK cells or T cells by chemical methods, using aphidicolin, and through shRNA knockdown of MCM10 in an NK cell line. We found that the CD56 bright subset of NK cells accumulates more DNA damage and replication stress during activation than CD56 dim NK cells or activated T cells. Aphidicolin treatment increases apoptosis of CD56bright NK cells through increased pan-caspase expression caspase cleavage and decreases perforin expression in surviving cells. This effect is modeled by shRNA mediated knockdown of MCM10, thus linking decreased helicase protein expression to replication stress and impaired NK cell function. These findings show that sensitivity to replication stress affects human NK cell survival and function and can contribute to NK cell deficiency.

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Section: Discussionmentioning

confidence: 90%

Replication stress in activated human NK cells induces sensitivity to apoptosis

Guilz,

Ahn,

Fatima

et al. 2023

Preprint

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“…Recently, it has been shown that iCIML-NK cells have an accumulation of unfit mitochondria, characterized by an increase of mitochondrial superoxide levels. 37 …”

Section: Discussionmentioning

confidence: 99%

Proteomic and phenotypic characteristics of memory-like natural killer cells for cancer immunotherapy

Arellano-Ballestero,

Zubiak,

Dally

et al. 2024

J Immunother Cancer

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BackgroundHuman and mouse natural killer (NK) cells have been shown to develop memory-like function after short-term exposure to the cocktail of IL-12/15/18 or to overnight co-culture with some tumor cell lines. The resulting cells retain enhanced lytic ability for up to 7 days as well as after cryopreservation, and memory-like NK cells (mlNK) have been shown to induce complete remissions in patients with hematological malignancies. No single phenotype has been described for mlNK and the physiological changes induced by the short-term cytokine or tumor-priming which are responsible for these enhanced functions have not been fully characterized. Here, we have generated mlNK by cytokine and tumor-priming to find commonalities to better define the nature of NK cell “memory” in vitro and, for the first time, in vivo.MethodsWe initiated mlNK in vitro from healthy donors with cytokines (initiated cytokine-induced memory-like (iCIML)-NK) and by tumor priming (TpNK) overnight and compared them by high-dimensional flow cytometry, proteomic and metabolomic profiling. As a potential mechanism of enhanced cytolytic function, we analyzed the avidity of binding of the mlNK to NK-resistant tumors (z-Movi). We generated TpNK from healthy donors and from cancer patients to determine whether mlNK generated by interaction with a single tumor type could enhance lytic activity. Finally, we used a replication-incompetent tumor cell line (INKmune) to treat patients with myeloid leukaemias to potentiate NK cell function in vivo.ResultsTumor-primed mlNK from healthy donors and patients with cancer showed increased cytotoxicity against multiple tumor cell lines in vitro, analogous to iCIML-NK cells. Multidimensional cytometry identified distinct memory-like profiles of subsets of cells with memory-like characteristics; upregulation of CD57, CD69, CD25 and ICAM1. Proteomic profiling identified 41 proteins restricted to mlNK cells and we identified candidate molecules for the basis of NK memory which can explain how mlNK overcome inhibition by resistant tumors. Finally, of five patients with myelodysplastic syndrome or refractory acute myeloid leukemia treated with INKmune, three responded to treatment with measurable increases in NK lytic function and systemic cytokines.ConclusionsNK cell “memory” is a physiological state associated with resistance to MHC-mediated inhibition, increased metabolic function, mitochondrial fitness and avidity to NK-resistant target cells.

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“…In a recent study, Terrén and colleagues reported that in vitro stimulated-adoptive NK cells had low viability compared to unstimulated cells. Although enhanced autophagy flux was detected after cytokines stimulation, NK cell survival was closely dependent on mitochondrial clearance, and low OPA1 levels and absence of mitophagy are responsible for a consequent accumulation of dysfunctional mitochondria and NK cell death [ 143 ]. This suggests a major role of both mitochondria dynamics and mitophagy in regulating NK cell effector functions and their transition into memory cells.…”

Section: Autophagy In Nk Cell Differentiationmentioning

confidence: 99%

Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies

Giansanti,

Theinert,

Boeing

et al. 2023

Mol Cancer

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Autophagy is an essential cellular homeostasis pathway initiated by multiple stimuli ranging from nutrient deprivation to viral infection, playing a key role in human health and disease. At present, a growing number of evidence suggests a role of autophagy as a primitive innate immune form of defense for eukaryotic cells, interacting with components of innate immune signaling pathways and regulating thymic selection, antigen presentation, cytokine production and T/NK cell homeostasis. In cancer, autophagy is intimately involved in the immunological control of tumor progression and response to therapy. However, very little is known about the role and impact of autophagy in T and NK cells, the main players in the active fight against infections and tumors. Important questions are emerging: what role does autophagy play on T/NK cells? Could its modulation lead to any advantages? Could specific targeting of autophagy on tumor cells (blocking) and T/NK cells (activation) be a new intervention strategy? In this review, we debate preclinical studies that have identified autophagy as a key regulator of immune responses by modulating the functions of different immune cells and discuss the redundancy or diversity among the subpopulations of both T and NK cells in physiologic context and in cancer.

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IL-12/15/18-induced cell death and mitochondrial dynamics of human NK cells

Cited by 8 publications

References 27 publications

Replication stress in activated human NK cells induces sensitivity to apoptosis

Replication stress in activated human NK cells induces sensitivity to apoptosis

Proteomic and phenotypic characteristics of memory-like natural killer cells for cancer immunotherapy

Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies

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