Interferon-γ Promotes Antibody-mediated Fratricide of Acute Myeloid Leukemia Cells

Fatehchand, Kavin; McMichael, Elizabeth L.; Reader, Brenda F.; Fang, Huiqing; Santhanam, Ramasamy; Gautam, Shalini; Elavazhagan, Saranya; Mehta, Preeti; Buteyn, Nathaniel J; Merchand-Reyes, Giovanna; Vasu, Sumithira; Mo, Xiaokui; Benson, Don M.; Blachly, James S.; Carson, William E.; Byrd, John C.; Butchar, Jonathan P.; Tridandapani, Susheela

doi:10.1074/jbc.m116.753145

Cited by 19 publications

(20 citation statements)

References 54 publications

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“…Interestingly, the levels of CD38 protein expression on NK cells and the magnitude of regulation upon Dara binding appear to be different among different donors (see Fig.3C), an effect that brings us to speculate that differences in the immune system of patients may be critical for the deepness of response to Dara, a hypothesis that will need further validation. In agreement with previous data, which have shown a pivotal role of Dara in inducing macrophage-mediated phagocytosis; 33,34 our results demonstrate specifically that direct NK cell activation by Dara induces monocyte activation and polarization, increasing the ability of this subpopulation to kill cancer cells. The macrophage T cell activation markers CD80/CD86, which were upregulated upon Dara treatment via NK cell activation, play a pivotal role not only for macrophage polarization but also as a critical costimulatory molecule in the initial step of T cell activation and survival, 35 through its binding to the T cell receptor CD28, a hypothesis that is fully consistent with what is observed in Dara-treated patients, as recently reported.…”

Section: Discussionsupporting

confidence: 93%

Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting

Viola¹,

Donà²,

Caserta³

et al. 2019

Preprint

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AbstractDaratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex-vivo and in vivo. In support of Dara’s immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.

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Section: Discussionsupporting

confidence: 93%

Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting

Viola¹,

Donà²,

Caserta³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Primary cell handling was done as described previously. [ 22 ] White blood cells apheresed from AML patients were obtained after written informed consent in accordance with the Declaration of Helsinki under a protocol approved by the institutional review board of The Ohio State University. Cells were stored in liquid nitrogen in 20% FBS and 10% DMSO until needed for experiments.…”

Section: Methodsmentioning

confidence: 99%

Active hexose-correlated compound enhances extrinsic-pathway-mediated apoptosis of Acute Myeloid Leukemic cells

et al. 2017

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Active Hexose Correlated Compound (AHCC) has been shown to have many immunostimulatory and anti-cancer activities in mice and in humans. As a natural product, AHCC has potential to create safer adjuvant therapies in cancer patients. Acute Myeloid Leukemia (AML) is the least curable and second-most common leukemia in adults. AML is especially terminal to those over 60 years old, where median survival is only 5 to 10 months, due to inability to receive intensive chemotherapy. Hence, the purpose of this study was to investigate the effects of AHCC on AML cells both in vitro and in vivo. Results showed that AHCC induced Caspase-3-dependent apoptosis in AML cell lines as well as in primary AML leukopheresis samples. Additionally, AHCC induced Caspase-8 cleavage as well as Fas and TRAIL upregulation, suggesting involvement of the extrinsic apoptotic pathway. In contrast, monocytes from healthy donors showed suppressed Caspase-3 cleavage and lower cell death. When tested in a murine engraftment model of AML, AHCC led to significantly increased survival time and decreased blast counts. These results uncover a mechanism by which AHCC leads to AML-cell specific death, and also lend support for the further investigation of AHCC as a potential adjuvant for the treatment of AML.

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“…They also showed that IFN-γ treatment promotes the myeloid differentiation and phagocytic activity of primary AML patient cells. The combination of IFN-γ and FCγR activation enhanced the production of granzyme B, suggesting that IFN-γ can induce AML cells to differentiate into immune effector cells ( 46 ).…”

Section: Type II Ifn (Ifn-γ)mentioning

confidence: 99%

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

2017

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Hematopoietic stem cells (HSCs) are a rare subset of bone marrow cells that usually exist in a quiescent state, only entering the cell cycle to replenish the blood compartment, thereby limiting the potential for errors in replication. Inflammatory signals that are released in response to environmental stressors, such as infection, trigger active cycling of HSCs. These inflammatory signals can also directly induce HSCs to release cytokines into the bone marrow environment, promoting myeloid differentiation. After stress myelopoiesis is triggered, HSCs require intracellular signaling programs to deactivate this response and return to steady state. Prolonged or excessive exposure to inflammatory cytokines, such as in prolonged infection or in chronic rheumatologic conditions, can lead to continued HSC cycling and eventual HSC loss. This promotes bone marrow failure, and can precipitate preleukemic states or leukemia through the acquisition of genetic and epigenetic changes in HSCs. This can occur through the initiation of clonal hematopoiesis, followed by the emergence preleukemic stem cells (pre-LSCs). In this review, we describe the roles of multiple inflammatory signaling pathways in the generation of pre-LSCs and in progression to myelodysplastic syndrome (MDS), myeloproliferative neoplasms, and acute myeloid leukemia (AML). In AML, activation of some inflammatory signaling pathways can promote the cycling and differentiation of LSCs, and this can be exploited therapeutically. We also discuss the therapeutic potential of modulating inflammatory signaling for the treatment of myeloid malignancies.

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Interferon-γ Promotes Antibody-mediated Fratricide of Acute Myeloid Leukemia Cells

Cited by 19 publications

References 54 publications

Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting

Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting

Active hexose-correlated compound enhances extrinsic-pathway-mediated apoptosis of Acute Myeloid Leukemic cells

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

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