Oncotarget

Research Papers: Immunology:

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

Johan Van den Bergh _, Yannick Willemen, Eva Lion, Heleen Van Acker, Hans De Reu, Sébastien Anguille, Herman Goossens, Zwi Berneman, Viggo Van Tendeloo and Evelien Smits

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Oncotarget. 2015; 6:44123-44133. https://doi.org/10.18632/oncotarget.6536

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Abstract

Johan Van den Bergh1, Yannick Willemen1, Eva Lion1, Heleen Van Acker1, Hans De Reu1, Sébastien Anguille1, Herman Goossens2, Zwi Berneman1, Viggo Van Tendeloo1,* and Evelien Smits1,3,*

1 Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

2 Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

3 Center for Oncological Research Antwerp, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

* shared senior authors

Correspondence to:

Johan Van den Bergh, email:

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

Received: September 15, 2015 Accepted: November 28, 2015 Published: December 09, 2015

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.


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