The Immunomodulatory Functions of Diacylglycerol Kinase ζ

Singh, Brenal K.; Kambayashi, Taku

doi:10.3389/fcell.2016.00096

Cited by 32 publications

(33 citation statements)

References 92 publications

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“…DGK-α and DGK-ζ have effects on macrophages, dendritic cells and T reg s (Singh and Kambayashi, 2016). In macrophages and dendritic cells, DKG-ζ deficiency was found to be associated with impaired secretion of inflammatory IL-12 and TNF and impaired Th1-responses.…”

Section: Further Considerations For the Development Of Dgk-inhibitionmentioning

confidence: 99%

DGK-α: A Checkpoint in Cancer-Mediated Immuno-Inhibition and Target for Immunotherapy

Noeßner

2017

Front. Cell Dev. Biol.

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Immunotherapy is moving to the forefront of cancer treatments owing to impressive durable responses achieved with checkpoint blockade antibodies and adoptive T-cell therapy. Still, improvements are necessary since, overall, only a small percentage of patients benefit from current therapies. Here, I summarize evidence that DGK-α may represent an immunological checkpoint suppressing the activity of cytotoxic immunocytes in the tumor microenvironment. DGK-inhibitors can restore the antitumor function of tumor-suppressed adaptive and innate cytotoxic immunocytes. The activity of DGK-inhibitors lays downstream of current checkpoint blockade antibodies. Thus, synergistic effects are expected from combination strategies. Moreover, DGK-inhibitors may permit a double-strike attack on tumor cells as DGK-inhibition may not only re-instate immunological tumor attack but also may harm tumor cells directly by interfering with oncogenic survival pathways. Together, DGK-inhibitors have very promising characteristics and may be beneficially included into the armamentarium of cancer immunotherapeutics.

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Section: Further Considerations For the Development Of Dgk-inhibitionmentioning

confidence: 99%

DGK-α: A Checkpoint in Cancer-Mediated Immuno-Inhibition and Target for Immunotherapy

Noeßner

2017

Front. Cell Dev. Biol.

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“…Although DGKaz KO enhanced effector function against mesothelioma (23), it significantly impaired the T-cell response against Listeria monocytogenes (24). Moreover, DGK KO in the mouse alters inflammatory functions of other immune cells such as dendritic cells and macrophages, which may affect T-cell biology (25,26). In addition to these issues, immunologic differences between human and mouse T cells exist.…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9-Mediated Knockout of DGK Improves Antitumor Activities of Human T Cells

et al. 2018

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The efficacy of T-cell therapy is inhibited by various tumor-associated immunosuppressive ligands and soluble factors. Such inhibitory signals turn specific T-cell signaling pathways on or off, impeding the anticancer functions of T cells. Many studies have focused on PD-1 or CTLA-4 blockade to invigorate T-cell functions through CD28/B7 signaling, but obtaining robust clinical outcomes remains challenging. In this study, we use CRISPR/Cas9 to potentiate T-cell function by increasing CD3 signaling via knockout of diacylglycerol kinase (DGK), an enzyme that metabolizes diacylglycerol to phosphatidic acid. Knockout of DGK augmented the effector functions of CAR-T cells via increased TCR signaling. DGK knockout from CAR-T cells rendered them resistant to soluble immunosuppressive factors such as TGFβ and prostaglandin E2 and sustained effector functions under conditions of repeated tumor stimulation. Moreover, DGK knockout caused significant regression of U87MGvIII glioblastoma tumors through enhanced effector functions in a xenograft mouse model. Collectively, our study shows that knockout of DGK effectively enhances the effector functions of CAR-T cells, suggesting that CRISPR/Cas9-mediated knockout of DGK could be applicable as part of a multifaceted clinical strategy to treat solid cancers. This novel study demonstrates efficient ablation of diacylglycerol kinase in human CAR-T cells that leads to improved antitumor immunity and may have significant impact in human cancer immunotherapy. .

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“…The pathogenesis of AML has been unclear and every effort to increase our understanding of AML pathogenesis is of great significance [17][18] . DGKZ is associated with a variety of malignant diseases in humans [19][20] and is also related to proliferation and apoptosis of T cells in the blood system [21][22][23] .With the popularity of precision medical advancement, stem cell technology, cell therapy technology, and the progress of new drugs, survival will greatly enhance in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of DGKZ induces apoptosis and G2/M phase arrest in human acute myeloid leukemia HL-60 cells

Tian

et al. 2018

Preprint

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Diacylglycerol kinase zeta (DGKZ) is associated with the pathogenesis of a variety of malignant diseases, but its biological function on acute myeloid leukemia (AML) has not been explored. This study was aimed to analyze apoptosis induced by Knockdown of DGKZ and its mechanism in human acute myeloid leukemia HL-60 cells.In the present study qRT-PCR was used to detect the expression of DGKZ in HL-60, THP-1, K562, H9, Jurkat and CD34 cell lines. DGKZ-shRNA lentiviral vector was established and used to infect acute myeloid leukemia HL-60 cells. Cell Counting Kit-8 (CCK-8) assay was used to determine the viability of HL-60 cells DGKZ knocked down. Apoptosis and cell cycle phase of HL-60 cells after DGKZ knockdown were evaluated by flow cytometry. Western blot analysis was performed to investigated the protein expression related to apoptosis and cell cycle. Results showed DGKZ expression were stable and higher in Jurkat, HL-60, THP-1,K562 leukemia cells than those of H9 and CD34 cells. Compared with cells of the shCtrl group, DGKZ was markedly knocked down in cells which were transfected with lentivirus encoding shRNA of DGKZ in HL-60 cells. DGKZ knockdown significantly inhibited the proliferation and induced cycle arrest at the G2/M phase in HL-60 cells. Western blot results indicated the expressions of caspase-3, caspase-8, and survivin markedly increased in HL-60 cells after knockdown of DGKZ. The results suggest Knockdown of DGKZ can inhibit proliferation of acute myeloid leukemia HL-60 cell caused cell cycle arrest at the G2/M phase through caspases pathway.

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The Immunomodulatory Functions of Diacylglycerol Kinase ζ

Cited by 32 publications

References 92 publications

DGK-α: A Checkpoint in Cancer-Mediated Immuno-Inhibition and Target for Immunotherapy

DGK-α: A Checkpoint in Cancer-Mediated Immuno-Inhibition and Target for Immunotherapy

CRISPR/Cas9-Mediated Knockout of DGK Improves Antitumor Activities of Human T Cells

Knockdown of DGKZ induces apoptosis and G2/M phase arrest in human acute myeloid leukemia HL-60 cells

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