Enhancement of antitumor potency of extracellular vesicles derived from natural killer cells by IL-15 priming. (January 2019)

• Record Type: Journal Article
• Authors: Zhu, Liya; Kalimuthu, Senthilkumar; Oh, Ji Min; Gangadaran, Prakash; Baek, Se Hwan; Jeong, Shin Young; Lee, Sang-Woo; Lee, Jaetae; Ahn, Byeong-Cheol
• Is Part Of: Biomaterials. Volume 190/191(2019)
• Page Start: 38
• Page End: 50
• Publication Date: 2019-01
• Subjects: Extracellular vesicles -- NK cells -- IL-15 -- Tumor targeting -- Immunotherapy -- Glioblastoma; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2018.10.034
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Purpose: Natural killer (NK) cells are the key subset of innate-immunity lymphocytes; they possess antitumor activities and are used for cancer immunotherapy. In a previous study, extracellular vehicles (EVs) from NK-92MI cells were isolated and exploited for their ability to kill human cancer cells in vitro and in vivo (multiple injection methods). Here, the potential of NK-cell–derived EVs (NK-EVs) for immunotherapy was improved by priming with interleukin (IL)-15. Methods: NK-EVs were isolated from the culture medium without or with IL-15 (NK-EVsIL-15 ) by ultracentrifugation and were purified via density gradient ultracentrifugation. In addition, NK-EVs and NK-EVsIL-15 were characterized by transmission electron microscopy, nanoparticle-tracking analysis, and western blotting. Flow cytometry, bioluminescence imaging, and a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay were performed for apoptosis, protein expression, cell proliferation, and cytotoxicity analyses. Furthermore, xenograft tumor–bearing mice were injected with PBS, NK-EVs, or NK-EVsIL-15 intravenously five times. Tumor growth was monitored using calipers and bioluminescence imaging. Toxicity of the nanoparticles was evaluated by measuring the body weight of the mice. Results: NK-EVsIL-15 showed significantly higher cytolytic activity toward human cancer cell lines (glioblastoma, breast cancer, and thyroid cancer) and simultaneously increased the expression of molecules associated with NK-cell cytotoxicity. When compared with NK-EVs, NK-EVsIL-15 significantly inhibited the growth of glioblastoma xenograft cells in mice. In addition, both NK-EVs and NK-EVsIL-15 were not significantly toxic to either normal cells or mice. Conclusion: IL-15 may improve the immunotherapeutic effects of NK-EVs, thus improving the applications of NK-EVs in the future.