Abstract
The contribution of natural killer (NK) cells to the treatment efficacy of dendritic cell (DC)-based cancer vaccines is being increasingly recognized. Much current efforts to optimize this form of immunotherapy are therefore geared towards harnessing the NK cell-stimulatory ability of DCs. In this study, we investigated whether generation of human monocyte-derived DCs with interleukin (IL)-15 followed by activation with a Toll-like receptor stimulus endows these DCs, commonly referred to as “IL-15 DCs”, with the capacity to stimulate NK cells. In a head-to-head comparison with “IL-4 DCs” used routinely for clinical studies, IL-15 DCs were found to induce a more activated, cytotoxic effector phenotype in NK cells, in particular in the CD56bright NK cell subset. With the exception of GM-CSF, no significant enhancement of cytokine/chemokine secretion was observed following co-culture of NK cells with IL-15 DCs. IL-15 DCs, but not IL-4 DCs, promoted NK cell tumoricidal activity towards both NK-sensitive and NK-resistant targets. This effect was found to require cell-to-cell contact and to be mediated by DC surface-bound IL-15. This study shows that DCs can express a membrane-bound form of IL-15 through which they enhance NK cell cytotoxic function. The observed lack of membrane-bound IL-15 on “gold-standard” IL-4 DCs and their consequent inability to effectively promote NK cell cytotoxicity may have important implications for the future design of DC-based cancer vaccine studies.
Highlights
The recent licensing of several high-profile cancer immunotherapy products, such as the dendritic cell (DC)-based prostate cancer vaccine sipuleucel-T, has further cemented immunotherapy as the fourth pillar in cancer treatment alongside the three traditional treatment optionsPLOS ONE | DOI:10.1371/journal.pone.0123340 May 7, 2015Enhancement of natural killer (NK) Cell Cytotoxicity by IL-15-Expressing DCsLeague against Cancer (Vlaamse Liga tegen Kanker, www.tegenkanker.be)
Phenotypic characterization revealed a marked increase in expression level of the different NK cell surface antigens studied (CD56, CD69, CD25, HLA-DR, NKG2D, NKp30 and NKp46) following 48-hr co-culture of NK cells with autologous IL-15 DCs, in contrast to IL-4 DCs which possessed very limited capacity to induce NK cell activation (Fig 1 and Table 1)
This effect was most pronounced in the CD56bright subset, where IL-15 DC stimulation resulted in a >5-fold increase in CD69 mean fluorescence intensity (MFI) compared to basal expression (Fig 1A; P
Summary
The recent licensing of several high-profile cancer immunotherapy products, such as the dendritic cell (DC)-based prostate cancer vaccine sipuleucel-T, has further cemented immunotherapy as the fourth pillar in cancer treatment alongside the three traditional treatment optionsPLOS ONE | DOI:10.1371/journal.pone.0123340 May 7, 2015Enhancement of NK Cell Cytotoxicity by IL-15-Expressing DCsLeague against Cancer (Vlaamse Liga tegen Kanker, www.tegenkanker.be). The recent licensing of several high-profile cancer immunotherapy products, such as the dendritic cell (DC)-based prostate cancer vaccine sipuleucel-T, has further cemented immunotherapy as the fourth pillar in cancer treatment alongside the three traditional treatment options. Enhancement of NK Cell Cytotoxicity by IL-15-Expressing DCs. League against Cancer (Vlaamse Liga tegen Kanker, www.tegenkanker.be). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
