Author(s):
|
Willemen, Y.; Bergh, J.M. Van den; Lion, E.; Anguille, S.; Roelandts, V.A.; Acker, H.H. Van; Heynderickx, S.D.; Stein, B.M.; Peeters, M.;
Figdor, C.G.
; Tendeloo, V.F. Van;
Vries, I.J.M. de
;
Adema, G.J.
; Berneman, Z.N.; Smits, E.L.
|
Subject:
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Radboudumc 2: Cancer development and immune defence RIMLS: Radboud Institute for Molecular Life Sciences |
Organization:
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Tumorimmunology Medical Oncology |
Journal title:
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Cancer Immunology Immunotherapy
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Abstract:
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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)-alpha, 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-alpha 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-alpha using mRNA electroporation enhances their ability to promote adaptive and innate anti-tumor immunity. Our results show that IFN-alpha 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-alpha secretion. Altogether, our findings mark IFN-alpha 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.
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