High-dimensional mass cytometry analysis of NK cell alterations in AML identifies a subgroup with adverse clinical outcome

Chrétien, Anne-Sophie; Devillier, Raynier; Granjeaud, Samuel; Cordier, Charlotte; Demerle, Clémence; Salem, N.; Wlosik, Julia; Orlanducci, Florence; Gorvel, Laurent; Fattori, Stéphane; Hospital, Marie‐Anne; Pakradouni, Jihane; Gregori, Emilie; Paul, Magali; Rochigneux, Philippe; Pagliardini, Thomas; Morey, Mathieu; Fauriat, Cyril; Dulphy, Nicolas; Toubert, Antoine; Luche, Hervé; Malissen, Marie; Blaise, Didier; Nunès, Jacques A.; Vey, Norbert; Olive, Daniel

doi:10.1073/pnas.2020459118

Cited by 40 publications

(34 citation statements)

References 51 publications

(79 reference statements)

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“…Contrary to HDs, in AML, we found a significantly altered distribution of NK cells with increased frequencies of PB- and BM-derived CD56 bright CD16 − and CD56 dim CD16 − NK cell populations. Overall, we observed a loss of CD56 expression on NK cells, which has also been observed by Chretien et al [ 10 ]. In addition, a reduction of cytotoxic NK cells was recently described in different hematological malignancies (including AML) and solid tumors, especially at the tumor sites [ 43 ].…”

Section: Discussionsupporting

confidence: 90%

“…The CD3 – CD56 dim CD16 − and CD3 – CD56 bright CD16 − NK cells have regulatory functions by secretion of different cytokines, such as interferon-gamma (IFN-y), upon exposure to the microenvironment [ 6 , 7 ]. The CD56 – CD16 + NK cells are defined as an unconventional NK cell subset increased in chronic infections and cancer and with significantly decreased effector functions [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Hypothesizing that NK cells are dysfunctional in AML [ 10 , 34 ], in this study, we aimed to characterize “exhaustion” patterns and functionality of NK cells derived from the peripheral blood (PB) and bone marrow (BM) of patients with AML. In contrast to the well-defined T cell exhaustion, a consensus on the characteristic features of NK cell “exhaustion” is missing [ 15 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

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Combined Blockade of TIGIT and CD39 or A2AR Enhances NK-92 Cell-Mediated Cytotoxicity in AML

Brauneck

Seubert

Wellbrock

et al. 2021

IJMS

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This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and peripheral blood cells from acute myeloid leukemia (AML) patients and healthy donors (HDs). Our data show that CD56dimCD16− and CD56brightCD16− NK cells represent the predominant NK cell subpopulations in AML, while the CD56dimCD16+ NK cells are significantly reduced compared to HDs. Moreover, TIGIT+ and PVRIG+ cells cluster on the CD56dimCD16+ subset whereas CD39+ and CD38+ cells do so on CD56brightCD16− NK cells in AML. Furthermore, functional effects of (co-)blockade of TIGIT and CD39 or A2AR on NK cell functionality were analyzed. These experiments revealed that the single blockade of the TIGIT receptor results in an increased NK-92 cell-mediated killing of AML cells in vitro. Combined targeting of CD39 or A2AR significantly augments the anti-TIGIT-mediated lysis of AML cells. Our data indicate that distinct NK cell subsets in AML exhibit different immunosuppressive patterns (via the TIGIT/PVRIG receptors and the purinergic pathway). In summary, we conclude that TIGIT, CD39, and A2AR constitute relevant inhibitory checkpoints of NK cells in AML patients. A combinatorial blockade synergistically strengthens NK-92 cell-mediated cytotoxicity. As inhibitors of TIGIT, CD39, and A2AR are clinically available, studies on their combined use could be conducted in the near future.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combined Blockade of TIGIT and CD39 or A2AR Enhances NK-92 Cell-Mediated Cytotoxicity in AML

Brauneck

Seubert

Wellbrock

et al. 2021

IJMS

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“…NK cells play a major role in the defense against AML cells. However, numerous studies, including ours, have reported defects in NK cells in AML patients which all severely impair the anti-tumor functions and affect the clinical outcomes (29)(30)(31)(32)(33)(34)(35). These defects include alteration of maturation, reduced cytotoxic functions, downregulation of triggering receptor expression or up-regulation of inhibitory/regulatory receptors, or down-regulation of transcription factors important for NK cell functions (29,30,36,37).…”

Section: Introductionmentioning

confidence: 84%

Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia

et al. 2021

Self Cite

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Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to restore NK cell potential. Here, we have used a mouse model of AML to gain insight into these mechanisms. We found that leukemia progression resulted in NK cell maturation defects and functional alterations. Next, we assessed NK cell cytokine signaling governing their behavior. We showed that NK cells from leukemic mice exhibit constitutive IL-15/mTOR signaling and type I IFN signaling. However, these cells failed to respond to IL-15 stimulation in vitro as illustrated by reduced activation of the mTOR pathway. Moreover, our data suggest that mTOR-mediated metabolic responses were reduced in NK cells from AML-bearing mice. Noteworthy, the reduction of mTOR-mediated activation of NK cells during AML development partially rescued NK cell metabolic and functional defects. Altogether, our data strongly suggest that NK cells from leukemic mice are metabolically and functionally exhausted as a result of a chronic cytokine activation, at least partially IL-15/mTOR signaling. NK cells from AML patients also displayed reduced IL-2/15Rβ expression and showed cues of reduced metabolic response to IL-15 stimulation in vitro, suggesting that a similar mechanism might occur in AML patients. Our study pinpoints the dysregulation of cytokine stimulation pathways as a new mechanism leading to NK cell defects in AML.

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“…Moreover, an accumulation of CD56 − CD16 + unconventional NK cells, which correlates with poor prognosis, is observed in AML. These NK cells had decreased NKG2A, NKp30, NKp46, NKG2D, DNAM-1 and CD96 [122]. Other contradictory results are observed.…”

Section: Variation Of Nk Cells In Aging and Cancermentioning

confidence: 90%

Inflammaging, an Imbalanced Immune Response That Needs to Be Restored for Cancer Prevention and Treatment in the Elderly

Serrano‐López

Martín-Antonio

2021

Cells

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Nowadays, new advances in society and health have brought an increased life expectancy. However, at the same time, aging comes with complications that impact the development of autoimmunity, neurodegenerative diseases and cancer. These complications affect the quality of life and impact the public health system. Specifically, with aging, a low-grade chronic sterile systemic inflammation with self-reactivity in the absence of acute infection occurs termed inflammaging. Inflammaging is related to an imbalanced immune response that can be either naturally acquired with aging or accelerated due to external triggers. Different molecules, metabolites and inflammatory forms of cell death are highly involved in these processes. Importantly, adoptive cellular immunotherapy is a modality of treatment for cancer patients that administers ex vivo expanded immune cells in the patient. The manipulation of these cells confers them enhanced proinflammatory properties. A general consequence of proinflammatory events is the development of autoimmune diseases and cancer. Herein, we review subsets of immune cells with a pertinent role in inflammaging,relevant proteins involved in these inflammatory events and external triggers that enhance and accelerate these processes. Moreover, we mention relevant preclinical studies that demonstrate associations of chronic inflammation with cancer development.

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High-dimensional mass cytometry analysis of NK cell alterations in AML identifies a subgroup with adverse clinical outcome

Cited by 40 publications

References 51 publications

Combined Blockade of TIGIT and CD39 or A2AR Enhances NK-92 Cell-Mediated Cytotoxicity in AML

Combined Blockade of TIGIT and CD39 or A2AR Enhances NK-92 Cell-Mediated Cytotoxicity in AML

Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia

Inflammaging, an Imbalanced Immune Response That Needs to Be Restored for Cancer Prevention and Treatment in the Elderly

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