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Title
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Transpresentation of interleukin-15 by IL-15/IL-15Ra mRNA-engineered human dendritic cells boosts antitumoral natural killer cell activity
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Author
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Abstract
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| 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-15Ra) using mRNA electroporation. The addition of IL-15Ra 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-gamma, 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-15Ra 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-15Ra mRNA-engineered designer DC. |
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Language
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English
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Source (journal)
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Oncotarget. - Albany, N.Y, 2010, currens
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Publication
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Albany, N.Y
:
Impact Journals
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2015
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ISSN
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1949-2553
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DOI
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10.18632/ONCOTARGET.6536
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Volume/pages
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6
:42
(2015)
, p. 44123-44133
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ISI
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000369908800008
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Full text (Publisher's DOI)
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Full text (open access)
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