IFNα signaling through PKC-θ is essential for antitumor NK cell function

Comet, Natalia Ramirez; Aguilo, Nacho; Rathore, Moeez Ghani; Catalán, Elena; Garaude, Johan; Uzé, Gilles; Naval, Javier; Pardo, Julián; Villalba, Martín; Anel, Alberto

doi:10.4161/21624011.2014.948705

Cited by 10 publications

(8 citation statements)

References 58 publications

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“…Two cytokine cocktails were compared during the expansion protocol, always in the presence of the feeder cells: IL-2 + IL-15 or IL-2 + IL-15 + IFN-α. The inclusion of IFN-α is justified as this stimulatory cytokine increases cytotoxic potential in mouse NK cells in comparison with IL-15 that was instead implicated in the maintenance of viability 38 . Figure 1 shows how the presence of the feeder cells was necessary for the efficient expansion of NK cells.…”

Section: Resultsmentioning

confidence: 99%

Expanded and activated allogeneic NK cells are cytotoxic against B-chronic lymphocytic leukemia (B-CLL) cells with sporadic cases of resistance

Calvo

Reina-Ortiz

Giraldos

et al. 2020

Sci Rep

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Adoptive transfer of allogeneic natural killer (NK) cells is becoming a credible immunotherapy for hematological malignancies. In the present work, using an optimized expansion/activation protocol of human NK cells, we generate expanded NK cells (eNK) with increased expression of CD56 and NKp44, while maintaining that of CD16. These eNK cells exerted significant cytotoxicity against cells from 34 B-CLL patients, with only 1 sample exhibiting resistance. This sporadic resistance did not correlate with match between KIR ligands expressed by the eNK cells and the leukemic cells, while cells with match resulted sensitive to eNK cells. This suggests that KIR mismatch is not relevant when expanded NK cells are used as effectors. In addition, we found two examples of de novo resistance to eNK cell cytotoxicity during the clinical course of the disease. Resistance correlated with KIR-ligand match in one of the patients, but not in the other, and was associated with a significant increase in PD-L1 expression in the cells from both patients. Treatment of one of these patients with idelalisib correlated with the loss of PD-L1 expression and with re-sensitization to eNK cytotoxicity. We confirmed the idelalisib-induced decrease in PD-L1 expression in the B-CLL cell line Mec1 and in cultured cells from B-CLL patients. As a main conclusion, our results reinforce the feasibility of using expanded and activated allogeneic NK cells in the treatment of B-CLL.

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Section: Resultsmentioning

confidence: 99%

Expanded and activated allogeneic NK cells are cytotoxic against B-chronic lymphocytic leukemia (B-CLL) cells with sporadic cases of resistance

Calvo

Reina-Ortiz

Giraldos

et al. 2020

Sci Rep

Self Cite

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“…Expression of TNF-related apoptosis-inducing ligand (TRAIL), which directly induces cell death [27] was specifically reduced in the absence of FcRγ (Fig 2C). The expression of protein kinase C theta (PKC-θ), which is activated by NK cell–activating receptors [28] and IFN-I signaling [29], and is required for the production of cytotoxic mediators was found to be reduced in Fcer1g –/– mice upon LCMV infection (Fig 2D).…”

Section: Resultsmentioning

confidence: 99%

NK cell–intrinsic FcεRIγ limits CD8+ T-cell expansion and thereby turns an acute into a chronic viral infection

Duhan

Hamdan

et al. 2019

PLoS Pathog

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During viral infection, tight regulation of CD8 + T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8 + T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g –/– mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8 + T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8 + T cells and that the lack of FcRγ in Fcer1g –/– mice leads to enhanced CD8 + T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell–activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8 + T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8 + T-cell functions during chronic LCMV infection.

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“…As a surrogate marker for degranulation we determined lysosome associated membrane protein 1 (LAMP‐1, CD107a) expression on the cell surface by flow cytometry . Since Mtb‐ antigen by itself failed to induce degranulation above background levels, we pre‐activated T‐cells with IFN‐α which is known to improve the degranulation capacity of NK‐cells . IFN‐α and Mtb ‐antigens synergize to activate antigen specific lymphocyte activation, including degranulation.…”

Section: Resultsmentioning

confidence: 99%

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

et al. 2018

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Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abltyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb). Our results demonstrate that dasatinib impaired proliferation, cytokine release (IFN-γ, TNF-α, GM-CSF), expression of granulysin and degranulation of cytotoxic effector molecules of human Mtb-specific T-lymphocytes by inhibition of lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation. Despite this profound inhibition of T-cell function, dasatinib suppressed growth of virulent Mtb in human macrophages co-cultured with autologous Mtb-specific T-cells (49±15%). Functional analysis suggested that growth inhibition is due to dasatinib-triggered lysosomal acidification inMtb-infected macrophages. These results highlight the significance of innate immune responses, i.e. acidification of lysosomes, which control the multiplication of intracellular bacteria despite the lack of efficient T-cell support. Keywords: Human primary cells r infection immunology r infection immunology r tuberculosis r T-cells r Tyrosine kinase inhibitorAdditional supporting information may be found online in the Supporting Information section at the end of the article.

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IFNα signaling through PKC-θ is essential for antitumor NK cell function

Cited by 10 publications

References 58 publications

Expanded and activated allogeneic NK cells are cytotoxic against B-chronic lymphocytic leukemia (B-CLL) cells with sporadic cases of resistance

Expanded and activated allogeneic NK cells are cytotoxic against B-chronic lymphocytic leukemia (B-CLL) cells with sporadic cases of resistance

NK cell–intrinsic FcεRIγ limits CD8+ T-cell expansion and thereby turns an acute into a chronic viral infection

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

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