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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Maghazachi AA, Al-Aoukaty A . Chemokines activate natural killer cells through heterotrimeric G-proteins: implications for the treatment of AIDS and cancer. FASEB J 1998; 12: 913–924.
Maghazachi AA . Compartmentalization of human natural killer cells. Mol Immunol 2005; 42: 523–529.
Maghazachi AA . Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol 2010; 341: 37–58.
Fauria C, Long EO, Ljunggren HG, Bryceson YT . Regulation of human NK-cell cytokine and chemokie production by target cell recognition. Blood 2010; 115: 2167–2176.
Ballas ZK, Buchta CM, Rosean TR, Heusel JW, Shey MR . Role of NK cell subsets in organ-specific murine melanoma metastasis. PLoS One 2013; 8: e65599.
Cheng M, Chen Y, Xiao W, Sun R, Tian Z . NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol 2013; 10: 230–252.
Maghazachi AA . Insights into seven and single transmembrane-spanning domain receptors and their signaling pathways in human natural killer cells. Pharmacol Rev 2005; 57: 339–357.
Raulet DH, Gasser S, Gowen BG, Deng W, Jung H . Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 2013; 31: 413–441.
Ljunggren HG, Kärre K . In search of the ‘missing self': MHC molecules and NK cell recognition. Immunol Today 1990; 11: 237–244.
Kappos L, Gold R, Miller DH, MacManus DG, Havrdova E, Limmroth V et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008; 372: 1463–1472.
Linker RA, Lee DH, Stangel M, Gold R . Fumarates for the treatment of multiple sclerosis: potential mechanisms of action and clinical studies. Expert Rev Neurother 2008; 8: 1683–1690.
Gold R, Linker RA, Stangel M . Fumaric acid and its esters: an emerging treatment for multiple sclerosis with antioxidative mechanism of action. Clin Immunol 2012; 142: 44–48.
Scannevin RH, Chollate S, Jung MY, Shakett M, Patel H, Bista P et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther 2012; 341: 274–284.
Lin SX, Lisi L, Dello Russo C, Polak PE, Sharp A, Weinberg G et al. The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro 2011; 3( 2).
Schilling S, Goelz S, Linker RA, Leuhder F, Gold R . Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol 2006; 145: 101–107.
Peng H, Guerau-de-Arellano M, Mehta VB, Yang Y, Huss DJ, Papenfuss TL et al. Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor κB (NF-κB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem 2012; 287: 28017–28026.
Ghoreschi K, Brück J, Kellerer C, Deng C, Peng H, Rothfuss O et al. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med 2011; 208: 2291–2303.
Loewe R, Valero T, Kremling S, Pratscher B, Kunstfeld R, Pehamberger H et al. Dimethylfumarate impairs melanoma growth and metastasis. Cancer Res 2006; 66: 11888–11896.
Høglund RA, Holmøy T, Harbo HF, Maghazachi AA . A one year follow-up study of natural killer and dendritic cells activities in multiple sclerosis patients receiving glatiramer acetate (GA). PLoS One 2013; 8: e62237.
Rolin J, Sand KL, Knudsen E, Maghazachi AA . FTY720 and SEW2871 reverse the inhibitory effect of S1P on natural killer cell mediated lysis of K562 tumor cells and dendritic cells but not on cytokine releases. Cancer Immunol Immunother 2010; 59: 575–586.
Alter G, Malenfant JM, Altfeld M . CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods 2004; 294: 15–22.
Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367: 1098–1107.
Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367: 1087–1097.
Lee DH, Gold R, Linker RA . Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. Int J Mol Sci 2012; 13: 11783–11803.
Valero T, Steele S, Neumüller K, Bracher A, Niederleithner H, Pehamberger H et al. Combination of dacarbazine and dimethylfumurate efficiently reduces melanoma lymph node metastasis. J Invest Deramtol 2010; 130: 1087–194.
Al-Jaderi Z, Maghazachi AA . Effects of vitamin D3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells. Toxins 2013; 5: 1932–1947.
Alvarez-Breckenridge CA, Yu J, Price R, Wojton J, Pradarelli J, Mao H et al. NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors. Nat Med 2012; 18: 1827–1834.
Glasner A, Ghadially H, Gur C, Stanietsky N, Tsukerman P, Enk J et al. Recognition and prevention of tumor metastasis by the NK receptor NKp46/NCR1. J Immunol 2012; 188: 2509–2515.
Halfteck GG, Elboim M, Gur C, Achdout H, Ghadially H, Mandelboim O . Enhanced in vivo growth of lymphoma tumors in the absence of the NK-activating receptor NKp46/NCR1. J Immunol 2009; 182: 2221–2230.
Hudspeth K, Silva-Santos B, Mavilio D . Natural cytotoxicity receptors: broader expression patterns and functions in innate and adptive immune cells. Front Immunol 2013; 4: 1–15.
Betts MR, Brenchley JM, Price DA, de Rosa SC, Douek DC, Roederer M et al. Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 2003; 281: 65–78.
Cohnen A, Chiang SC, Stojanovic A, Schmidt H, Claus M, Saftig P et al. Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage. Blood 2013; 122: 1411–1418.
Dibbert S, Clement B, Skak-Nielsen T, Mrowietz U, Rostami-Yazdi M . Detection of fumarate-glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism. Arch Dermatol Res 2013; 305: 447–451.
Sherry RM, Rosenberg SA, Yang JC . Relapse after response to interleukin-2-based immunotherapy: patterns of progression and response to retreatment. J Immunother 1991; 10: 371–375.
Tang H, Lu JY, Zheng X, Yang Y, Reagan JD . The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist. Biochem Biophys Res Commun 2008; 375: 562–565.
Chen H, Assmann JC, Krenz A, Rahman M, Grimm M, Karsten CM et al. Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE. J Clin Invest 2014; 124: 2188–2192.
Acknowledgements
This work was supported through funding from the University of Oslo, Biogen-Idec Global, Inc. Vivi Irene Hansens Funds for Systemic Lupus Erythematosus.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
Lars-Egil Fallang and Glen Gundersen are employees of Biogen-Idec Global, Inc., Norway. Biogen-Idec did not interfere with the design of the experiments or with the analysis and presentation of the data.
Rights and permissions
About this article
Cite this article
Vego, H., Sand, K., Høglund, R. et al. Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a. Cell Mol Immunol 13, 57–64 (2016). https://doi.org/10.1038/cmi.2014.114
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cmi.2014.114