Abstract
Dendritic cell (DC) vaccination has demonstrated potential in clinical trials as a new effective cancer treatment, but objective and durable clinical responses are confined to a minority of patients. Interferon (IFN)-α, a type-I IFN, can bolster anti-tumor immunity by restoring or increasing the function of DCs, T cells and natural killer (NK) cells. Moreover, type-I IFN signaling on DCs was found to be essential in mice for tumor rejection by the innate and adaptive immune system. Targeted delivery of IFN-α by DCs to immune cells could boost the generation of anti-tumor immunity, while avoiding the side effects frequently associated with systemic administration. Naturally circulating plasmacytoid DCs, major producers of type-I IFN, were already shown capable of inducing tumor antigen-specific T cell responses in cancer patients without severe toxicity, but their limited number complicates their use in cancer vaccination. In the present work, we hypothesized that engineering easily generated human monocyte-derived mature DCs to secrete IFN-α using mRNA electroporation enhances their ability to promote adaptive and innate anti-tumor immunity. Our results show that IFN-α mRNA electroporation of DCs significantly increases the stimulation of tumor antigen-specific cytotoxic T cell as well as anti-tumor NK cell effector functions in vitro through high levels of IFN-α secretion. Altogether, our findings mark IFN-α mRNA-electroporated DCs as potent inducers of both adaptive and innate anti-tumor immunity and pave the way for clinical trial evaluation in cancer patients.
Abbreviations
- 7-AAD:
-
7-Amino actinomycin D
- ANOVA:
-
Analysis of variance
- CFSE:
-
Carboxyfluorescein succinimidyl ester
- DC:
-
Dendritic cell
- EP:
-
Electroporated
- FBS:
-
Fetal bovine serum
- HLA:
-
Human leukocyte antigen
- IFN:
-
Interferon
- IL:
-
Interleukin
- IMDM:
-
Iscove’s modified Dulbecco’s medium
- mAb:
-
Monoclonal antibody
- MLR:
-
Mixed lymphocyte reaction
- NK:
-
Natural killer
- PBMC:
-
Peripheral blood mononuclear cells
- PHA:
-
Phytohemagglutinin
- PI:
-
Propidium iodide
- RPMI:
-
Roswell Park Memorial Institute
- WT1:
-
Wilms’ tumor 1
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Acknowledgments
The authors would like to thank Maaike W.G. Looman for excellent technical advice. This work was supported in part by grants from the Dutch Cancer Society (KWF; 2009-4402), the Research Foundation—Flanders (FWO), the Foundation against Cancer (STK), and the Methusalem program of the Flemish Government (attributed to Prof. H. Goossens). Y. Willemen is a PhD fellow of the agency for Innovation by Science and Technology (IWT). E.L.J. Smits was supported by an FWO postdoctoral fellowship and a training grant from the Belgian Hematological Society. S. Anguille was funded by an Emmanuel van der Schueren grant from the Flemish League against Cancer (VLK).
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The authors declare that they have no conflict of interest.
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Willemen, Y., Van den Bergh, J.M.J., Lion, E. et al. Engineering monocyte-derived dendritic cells to secrete interferon-α enhances their ability to promote adaptive and innate anti-tumor immune effector functions. Cancer Immunol Immunother 64, 831–842 (2015). https://doi.org/10.1007/s00262-015-1688-2
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DOI: https://doi.org/10.1007/s00262-015-1688-2