Transpresentation of interleukin-15 by IL-15/IL-15Rα mRNA-engineered human dendritic cells boosts antitumoral natural killer cell activity

Oncotarget. 2015 Dec 29;6(42):44123-33. doi: 10.18632/oncotarget.6536.


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.

Keywords: IL-15 receptor α; Immune response; Immunity; Immunology and Microbiology Section; dendritic cells; interleukin-15 transpresentation; mRNA elektroporation; natural killer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cancer Vaccines / immunology
  • Cell Communication*
  • Coculture Techniques
  • Cytotoxicity, Immunologic
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Dendritic Cells / transplantation
  • Electroporation
  • Genetic Engineering
  • Granzymes / metabolism
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / metabolism
  • Interleukin-15 / genetics
  • Interleukin-15 / metabolism*
  • K562 Cells
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / immunology
  • Leukemia, Myeloid, Acute / therapy*
  • Lymphocyte Activation*
  • Perforin / metabolism
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Receptors, Interleukin-15 / genetics
  • Receptors, Interleukin-15 / metabolism*
  • Remission Induction
  • Signal Transduction
  • Time Factors
  • Transfection


  • Cancer Vaccines
  • IFNG protein, human
  • IL15 protein, human
  • IL15RA protein, human
  • Interleukin-15
  • RNA, Messenger
  • Receptors, Interleukin-15
  • Perforin
  • Interferon-gamma
  • GZMB protein, human
  • Granzymes