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.
Highlights
As the main orchestrators of the immune system, dendritic cells (DC) are ideal candidates in the design of immunotherapeutic strategies to treat cancer patients
Electroporation of DC with IL‐15 mRNA results in significant IL‐15 secretion, but IL‐15Rα is required for membrane expression of IL‐15
Regarding IL‐15Rα expression, we demonstrate that this molecule is already present on monocyte-derived IL‐4 DC and that the expression of IL‐15Rα is only statistically significantly upregulated when both IL‐15 and IL‐15Rα mRNA are cotransfected into the DC (Supplemental Figure 1)
Summary
As the main orchestrators of the immune system, dendritic cells (DC) are ideal candidates in the design of immunotherapeutic strategies to treat cancer patients. For this reason, DC based vaccination is being explored to improve clinical outcome of various cancer patients. As reported by our and other research groups, DC based immunotherapy was shown in clinical trials to be safe and able to induce antitumor immune responses [1, 2]. Combinatorial methods to awake or restore impaired NK cell functions may improve clinical outcome in DC vaccine trials [11]
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