IL-2 costimulation enables statin-mediated activation of human NK cells, preferentially through a mechanism involving CD56+ dendritic cells

Cancer Res. 2010 Dec 1;70(23):9611-20. doi: 10.1158/0008-5472.CAN-10-1968. Epub 2010 Oct 14.


Statins are inhibitors of cholesterol biosynthesis and protein prenylation that also have been studied in cancer therapy and chemoprevention. With regard to natural killer (NK) cells, only inhibitory effects of statins such as suppression of granule exocytosis have been reported so far. In this study, we show that statins can cooperate with IL-2 to potently induce the activation of CD56(dim) NK cells in a synergistic, time- and dose-dependent fashion. Supplementation experiments revealed that the statin effect was specific to inhibition of their target hydroxymethylglutaryl coenzyme A reductase and that downstream depletion of geranylgeranyl pyrophosphate was responsible for cooperating with IL-2 in NK cell activation. Mechanistic studies revealed that CD56(+)HLA-DR(+)CD14(+) dendritic cell (DC)-like accessory cells mediated the ability of statin to activate NK cells. In contrast, BDCA-1(+) (CD1c(+)) myeloid DCs, which partially expressed CD56, were somewhat less potent. Conventional blood monocytes, which lack CD56, exhibited the lowest accessory cell capacity. NK cell IFN-γ production was IL-12 independent but required endogenous IL-18, IL-1β, and caspase-1 activity. Statins directly induced apoptosis in human cancer cell lines and cooperated with NK cell-derived IFN-γ to generate potent cytotoxic antitumor effects in vitro even in the presence of statin-mediated inhibitory effects on granule exocytosis. Our work reveals novel and unexpected immunomodulatory properties of statins, which might be harnessed for the treatment of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • CD56 Antigen / immunology
  • CD56 Antigen / metabolism
  • Caspase 1 / immunology
  • Caspase 1 / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Flow Cytometry
  • Humans
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-18 / immunology
  • Interleukin-18 / metabolism
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism
  • Interleukin-2 / metabolism
  • Interleukin-2 / pharmacology*
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lovastatin / analogs & derivatives
  • Lovastatin / chemistry
  • Lovastatin / pharmacology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Molecular Structure
  • Simvastatin / chemistry
  • Simvastatin / pharmacology
  • Time Factors


  • CD56 Antigen
  • Interleukin-18
  • Interleukin-1beta
  • Interleukin-2
  • mevastatin
  • Interferon-gamma
  • Lovastatin
  • Simvastatin
  • Caspase 1