Cancer Immunology, Immunotherapy

, Volume 63, Issue 6, pp 627–641

Immunomodulatory activity of commonly used drugs on Fc-receptor-mediated human natural killer cell activation

  • Jakob Theorell
  • Anna-Lena Gustavsson
  • Bianca Tesi
  • Kristmundur Sigmundsson
  • Hans-Gustaf Ljunggren
  • Thomas Lundbäck
  • Yenan T. Bryceson
Original Article

DOI: 10.1007/s00262-014-1539-6

Cite this article as:
Theorell, J., Gustavsson, AL., Tesi, B. et al. Cancer Immunol Immunother (2014) 63: 627. doi:10.1007/s00262-014-1539-6

Abstract

Natural killer (NK) cells mediate defense against neoplastic as well as infected cells. Yet, how their effector functions are affected by the large variety of pharmacological compounds commonly in use has not been investigated systematically. Here, we screened 1,200 in-use or previously approved drugs for their biological effect on freshly isolated human peripheral blood-derived NK cells. Mimicking antibody-dependent cellular cytotoxicity (ADCC), known to be important in antibody-based immunotherapies against, e.g., human malignancies, the cells were stimulated by Fc-receptor (CD16) engagement. Cellular responses were assessed by flow cytometry. Fifty-six compounds that significantly inhibited and twelve that enhanced one or more of the readouts of adhesion, exocytosis, and chemokine production were identified and confirmed as hits. Among the confirmed inhibitors, 80 % could be assigned to one of seven major pharmacological classes. These classes were β2-adrenergic agonists, prostaglandins, phosphodiesterase-4 inhibitors, Ca2+-channel blockers, histamine H1-receptor antagonists, serotonin/dopamine receptor antagonists, and topoisomerase inhibitors that displayed distinct inhibitory patterns on NK cell responses. Among observed enhancers, interestingly, two ergosterol synthesis inhibitors were identified that specifically promoted exocytosis. In summary, these results provide a comprehensive knowledge base of the effect known drugs have on NK cells. More specifically, they provide an overview of drugs that may modulate NK cell-mediated ADCC in the context of clinical immunotherapies.

Keywords

Humans Natural killer cells Cytotoxicity CD107a Small molecule screening Prestwick Chemical Library 

Abbreviations

ADCC

Antibody-dependent cellular cytotoxicity

DMSO

Dimethylsulfoxide

FBS

Fetal bovine serum

FSC-H

Forward scatter height

ITAM

Immunoreceptor tyrosine-based activation motif

IFN

Interferon

LFA

Leukocyte functional antigen

MIP

Macrophage-inducible protein

NK

Natural killer cells

PBMC

Peripheral blood mononuclear cells

PBS

Phosphate-buffered saline

PDE

Phosphodiesterase

SSC-H

Side scatter height

TNF

Tumor necrosis factor

Supplementary material

262_2014_1539_MOESM1_ESM.pdf (5.7 mb)
Supplementary material 1 (PDF 5,833 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jakob Theorell
    • 1
  • Anna-Lena Gustavsson
    • 2
  • Bianca Tesi
    • 3
    • 4
  • Kristmundur Sigmundsson
    • 2
  • Hans-Gustaf Ljunggren
    • 1
  • Thomas Lundbäck
    • 2
  • Yenan T. Bryceson
    • 1
    • 5
  1. 1.Department of Medicine, Centre for Infectious Medicine, F59, Karolinska InstitutetKarolinska University Hospital HuddingeStockholmSweden
  2. 2.Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine, Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
  3. 3.Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska InstitutetKarolinska University Hospital SolnaStockholmSweden
  4. 4.Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska InstitutetKarolinska University Hospital SolnaStockholmSweden
  5. 5.Broegelmann Research Laboratory, Institute of Clinical SciencesUniversity of BergenBergenNorway