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01.06.2014 | Original Article | Ausgabe 6/2014

Cancer Immunology, Immunotherapy 6/2014

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

Zeitschrift:
Cancer Immunology, Immunotherapy > Ausgabe 6/2014
Autoren:
Jakob Theorell, Anna-Lena Gustavsson, Bianca Tesi, Kristmundur Sigmundsson, Hans-Gustaf Ljunggren, Thomas Lundbäck, Yenan T. Bryceson
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00262-014-1539-6) contains supplementary material, which is available to authorized users.
The authors of this paper report on their NK assays transparently and comprehensively as per field-wide consensus, allowing the community a full understanding and interpretation of presented data as well as a comparison of data between groups. The electronic supplementary materials of this publication include a MIANKA checklist. For more details, see http://​miataproject.​org/​.

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.

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Zusatzmaterial
Supplementary material 1 (PDF 5,833 kb)
262_2014_1539_MOESM1_ESM.pdf
Literatur
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