title: Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a.
abstract: Dimethyl fumarate (DMF) is a new drug used to treat multiple sclerosis (MS) patients. Here, we examined the effects of DMF and the DMF metabolite monomethyl fumarate (MMF) on various activities of natural killer (NK) cells. We demonstrated that MMF augments the primary CD56(+), but not CD56(-), NK cell lysis of K562 and RAJI tumor cells. MMF induced NKp46 expression on the surface of CD56(+), but not CD56(-), NK cells after incubation for 24 h. This effect was closely correlated with the upregulation of CD107a expression on the surface of CD56(+) NK cells and the induction of Granzyme B release from these cells through this metabolite. An anti-NKp46 antibody inhibited the MMF-induced upregulation of CD107a and the lysis of tumor cells through CD56(+) NK cells. Thus, these results are the first to show that MMF augments CD56(+) NK cell lysis of tumor target cells, an effect mediated through NKp46. This novel effect suggests the use of MMF for therapeutic and/or preventive protocols in cancer.
authors.affiliation: Department of Physiology, Institute of Medical Basic Sciences, University of Oslo, Oslo, Norway.
authors.forename: Heidi
authors.initials: H
authors.lastname: Vego
authors.affiliation: Department of Physiology, Institute of Medical Basic Sciences, University of Oslo, Oslo, Norway.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Sand
authors.affiliation: Department of Physiology, Institute of Medical Basic Sciences, University of Oslo, Oslo, Norway.
authors.forename: Rune A
authors.initials: RA
authors.lastname: Høglund
authors.affiliation: Medical Department, Biogen Idec Norway AS, Oslo, Norway.
authors.forename: Lars-Egil
authors.initials: LE
authors.lastname: Fallang
authors.affiliation: Medical Department, Biogen Idec Norway AS, Oslo, Norway.
authors.forename: Glenn
authors.initials: G
authors.lastname: Gundersen
authors.affiliation: Department of Neurology, Akershus University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Trygve
authors.initials: T
authors.lastname: Holmøy
authors.affiliation: Department of Physiology, Institute of Medical Basic Sciences, University of Oslo, Oslo, Norway.
authors.forename: Azzam A
authors.initials: AA
authors.lastname: Maghazachi
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019002:CD56 Antigen / Q000235:genetics / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D005650:Fumarates / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic; D053804:Granzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D008298:Maleates / Q000494:pharmacology*; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D015398:Signal Transduction
chemical_list: D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D019002:CD56 Antigen; D005650:Fumarates; D052118:Lysosomal-Associated Membrane Protein 1; D008298:Maleates; C522918:NCAM1 protein, human; C112260:NCR1 protein, human; C431710:NCR3 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; C073341:citraconic acid; D053804:Granzymes; D000069462:Dimethyl Fumarate