title: Transpresentation of interleukin-15 by IL-15/IL-15Rα mRNA-engineered human dendritic cells boosts antitumoral natural killer cell activity.
abstract: In cancer immunotherapy, the use of dendritic cell (DC)-based vaccination strategies can improve overall survival, but until now durable clinical responses remain scarce. To date, DC vaccines are designed primarily to induce effective T-cell responses, ignoring the antitumor activity potential of natural killer (NK) cells. Aiming to further improve current DC vaccination outcome, we engineered monocyte-derived DC to produce interleukin (IL)-15 and/or IL-15 receptor alpha (IL-15Rα) using mRNA electroporation. The addition of IL-15Rα to the protocol, enabling IL-15 transpresentation to neighboring NK cells, resulted in significantly better NK-cell activation compared to IL-15 alone. Next to upregulation of NK-cell membrane activation markers, IL-15 transpresentation resulted in increased NK-cell secretion of IFN-γ, granzyme B and perforin. Moreover, IL-15-transpresenting DC/NK cell cocultures from both healthy donors and acute myeloid leukemia (AML) patients in remission showed markedly enhanced cytotoxic activity against NK cell sensitive and resistant tumor cells. Blocking IL-15 transpresentation abrogated NK cell-mediated cytotoxicity against tumor cells, pointing to a pivotal role of IL-15 transpresentation by IL-15Rα to exert its NK cell-activating effects. In conclusion, we report an attractive approach to improve antitumoral NK-cell activity in DC-based vaccine strategies through the use of IL-15/IL-15Rα mRNA-engineered designer DC.
authors.affiliation: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Van den Bergh
authors.affiliation: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Willemen
authors.affiliation: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Lion
authors.affiliation: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Heleen
authors.initials: H
authors.lastname: Van Acker
authors.affiliation: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: De Reu
authors.affiliation: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Anguille
authors.affiliation: Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Herman
authors.initials: H
authors.lastname: Goossens
authors.affiliation: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Zwi
authors.initials: Z
authors.lastname: Berneman
authors.affiliation: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Viggo
authors.initials: V
authors.lastname: Van Tendeloo
authors.affiliation: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.|Center for Oncological Research Antwerp, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Evelien
authors.initials: E
authors.lastname: Smits
mesh_terms: D019496:Cancer Vaccines / Q000276:immunology; D002450:Cell Communication; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D018274:Electroporation; D005818:Genetic Engineering; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D054353:Perforin / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D053647:Receptors, Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D012074:Remission Induction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D019496:Cancer Vaccines; C573415:IFNG protein, human; C569274:IL15 protein, human; C508024:IL15RA protein, human; D019409:Interleukin-15; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D054353:Perforin; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes
keywords: IL-15 receptor α; Immune response; Immunity; Immunology and Microbiology Section; dendritic cells; interleukin-15 transpresentation; mRNA elektroporation; natural killer cells