PT - JOURNAL ARTICLE AU - Choi, Yeon Ho AU - Lim, Eun Jin AU - Kim, Se Wha AU - Moon, Yong Wha AU - Park, Kyung Soon AU - An, Hee-Jung TI - IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells AID - 10.1186/s40425-019-0652-7 DP - 2019 Dec 01 TA - Journal for ImmunoTherapy of Cancer PG - 168 VI - 7 IP - 1 4099 - http://jitc.bmj.com/content/7/1/168.short 4100 - http://jitc.bmj.com/content/7/1/168.full SO - J Immunother Cancer2019 Dec 01; 7 AB - Background Natural killer (NK) cells are an emerging new tool for cancer immunotherapy. To develop NK cell therapeutics from peripheral blood mononuclear cells (PBMCs) of healthy donors, substantial expansion of primary NK cells is necessary because of the very low number of these cells in peripheral blood. In this study, we aimed to investigate the effect of various cytokine alone or combinations, in expanded NK cells and to analyze the synergetic effect of cytokine combinations.Methods Human NK cells were isolated from healthy donor PBMC. Purified NK cells were stimulated with single cytokines or combinations of IL-2, IL-15, IL-18, and IL-27. The expanded NK cells were characterized by flow cytometry, cytotoxicity assay, calcein AM assay and Western blot.Results We investigated the synergistic effects of each cytokine, namely, IL-2, IL-15, IL-18, and IL-27, on human NK cells isolated from PBMCs of healthy donors and cultured for 21 days. We identified that IL-15/IL-18/IL-27-mediated activation of NK cells most potently increased NK cell proliferation, cytotoxicity, and IFN-ɣ secretion compared with the activation observed with other treatments, including IL-2, IL-15, and IL-15/IL-18. Additionally, the expression of DNAM-1, NKG2D, CD69, and natural cytotoxicity receptors (NCRs; NKp30 and NKp44) increased on day 21 compared to that on day 0, demonstrating the activation of NK cells. In vitro, expanded NK cells were highly cytotoxic against cancer cells, displaying increased perforin and granzyme B accumulation.Conclusions Taken together, these results indicated that IL-27 can synergize on NK cell expansion and activation with IL-15 and IL-18. In addition, we described an improved culture method for ex vivo expansion of human NK cells with IL-15/IL-18/IL-27 stimulation and characterized the response of NK cells to this stimulation.A correction to this article is available online at https://doi.org/10.1186/s40425-019-0688-8.Abbreviations:CDCluster of differentiationCTLA-4Cytotoxic T lymphocyte-associated antigen 4ELISAEnzyme-linked immunosorbent assayIFN-γInterferon gammaILInterleukinKIRKiller cell immunoglobulin-like receptorMHCMajor histocompatibility complexNCRsNatural cytotoxicity receptorsNK cellsNatural killer cellsNKG2DNatural killer group 2DPBMCsPeripheral blood mononuclear cellPBSPhosphate buffered salinePD-1Programmed death-1