Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

Vego, Heidi; Sand, Kristin L.; Høglund, Rune Alexander; Fallang, Lars Egil; Gundersen, Glenn; Holmøy, Trygve; Maghazachi, Azzam A.

doi:10.1038/cmi.2014.114

Cited by 31 publications

(33 citation statements)

References 36 publications

(41 reference statements)

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“…Further antitumorigenic action of DMF could be demonstrated for glioblastoma and colon carcinoma cells . In addition, recent research demonstrated that the DMF metabolite MMF fortifies CD56 + NK cell lysis of tumor cells via degranulation and upregulation of NKp46 and CD107a . All these results illustrate that DMF seems to have potential antitumorigenic effects.…”

Section: Introductionmentioning

confidence: 84%

Dimethylfumarate effectively inhibits lymphangiogenesis via p21 induction and G1 cell cycle arrest

Valesky

Hrgović

Doll

et al. 2016

Experimental Dermatology

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Different pathologies, such as lymphoedema, cancer or psoriasis, are associated with abnormal lymphatic vessel formation. Therefore, influencing lymphangiogenesis is an interesting target. Recent evidence suggests that dimethylfumarate (DMF), an antipsoriatic agent, might have antitumorigenic and antilymphangiogenic properties. To prove this assumption, we performed proliferation and functional assays with primary human dermal lymphendothelial cells (DLEC). We could demonstrated that DMF suppresses DLEC proliferation and formation of capillary-like structures. Underlying apoptotic mechanisms could be ruled out. Cell cycle analysis demonstrated a pronounced G1-arrest. Further evaluations revealed increases in p21 expression. In addition, DMF suppressed Cyclin D1 and Cyclin A expression in a concentration-dependent manner. p21 knockdown experiments demonstrated a p21-dependent mechanism of regulation. Further analysis showed an increased p21 mRNA expression after DMF treatment. This transcriptional regulation was enforced by post-transcriptional and post-translational mechanisms. In addition, we could demonstrate that the combination of a proteasomal inhibitor and DMF superinduced the p21 expression. Hence, DMF is a new antilymphangiogenic compound and might be used in various illnesses associated with increased lymphangiogenesis.

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Section: Introductionmentioning

confidence: 84%

Dimethylfumarate effectively inhibits lymphangiogenesis via p21 induction and G1 cell cycle arrest

Valesky

Hrgović

Doll

et al. 2016

Experimental Dermatology

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“…NK cell activation requires the integration of signals from activating and inhibitory receptors [ 12 , 57 , 58 ]. Our cultured NK cells express numerous activating receptors (NKp46, NKp30, and NKG2D) and co-activating receptors (SFRs) to ensure their function.…”

Section: Discussionmentioning

confidence: 99%

Programmed differentiated natural killer cells kill leukemia cells by engaging SLAM family receptors

et al. 2017

Oncotarget

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Natural killer (NK) cells are important innate immune cells that can directly kill transformed or virus-infected cells. The adoptive transfer of NK cells has been used to treat hematological malignancies; however, the limited sources and quantities of NK cells have restricted their clinical application. Here, we acquired sufficient quantities of functional NK cells from CD34+ cells treated with a cytokine cocktail. Microarray analysis of the cultured cells revealed a two-stage pattern of programmed differentiation during NK cell development. Different transcription factors were enriched during these two stages, suggesting that preparation of progenitors committed to the NK cell lineage occurs in program 1, while NK cell transformation and maturation occur in program 2. Cultured NK cells highly expressed signaling lymphocytic activation molecule (SLAM) family receptors (SFRs), while leukemia cells expressed SFR ligands. The engagement of these SFRs strengthened the cytotoxicity of NK cells toward leukemia cells. These results demonstrate a simple method of obtaining sufficient NK cells for clinical application, and have categorized NK cell differentiation according to commitment and transformation programs. Moreover, the binding between SFRs on NK cells and their ligands on leukemia cells suggests a new basis for NK cell therapy for treatment of leukemia.

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“…Several cytokines and immunomodulatory drugs, such as the common g-chain family of cytokines (interleukin (IL)-2, IL-7, IL-15, and IL-21), thalidomide, and pomalidomide, boost NK-cell cytotoxicity [43,44]. However, the targets of these cytokines and drugs vary [45].…”

Section: Cytokines and Immunomodulatory Drugsmentioning

confidence: 99%

Challenges of NK cell-based immunotherapy in the new era

2018

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Natural killer cells (NKs) have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells (PBMCs), stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.

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Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

Cited by 31 publications

References 36 publications

Dimethylfumarate effectively inhibits lymphangiogenesis via p21 induction and G1 cell cycle arrest

Dimethylfumarate effectively inhibits lymphangiogenesis via p21 induction and G1 cell cycle arrest

Programmed differentiated natural killer cells kill leukemia cells by engaging SLAM family receptors

Challenges of NK cell-based immunotherapy in the new era

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