title: Immunomodulatory activity of commonly used drugs on Fc-receptor-mediated human natural killer cell activation.
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, Ca(2+)-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.
authors.affiliation: Department of Medicine, Centre for Infectious Medicine, F59, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Theorell
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Gustavsson
authors.forename: Bianca
authors.initials: B
authors.lastname: Tesi
authors.forename: Kristmundur
authors.initials: K
authors.lastname: Sigmundsson
authors.forename: Hans-Gustaf
authors.initials: HG
authors.lastname: Ljunggren
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundbäck
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D057166:High-Throughput Screening Assays; D006801:Humans; D007111:Immunity, Cellular; D007155:Immunologic Factors / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D004364:Pharmaceutical Preparations / Q000032:analysis / Q000378:metabolism*; D011961:Receptors, Fc / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D004364:Pharmaceutical Preparations; D011961:Receptors, Fc