title: Engineering monocyte-derived dendritic cells to secrete interferon-α enhances their ability to promote adaptive and innate anti-tumor immune effector functions.
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.
authors: Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, Antwerp, 2610, Belgium, yannick.willemen@uantwerp.be.
authors: Yannick
authors: Y
authors: Willemen
authors: Johan M J
authors: JM
authors: Van den Bergh
authors: Eva
authors: E
authors: Lion
authors: Sébastien
authors: S
authors: Anguille
authors: Vicky A E
authors: VA
authors: Roelandts
authors: Heleen H
authors: HH
authors: Van Acker
authors: Steven D I
authors: SD
authors: Heynderickx
authors: Barbara M H
authors: BM
authors: Stein
authors: Marc
authors: M
authors: Peeters
authors: Carl G
authors: CG
authors: Figdor
authors: Viggo F I
authors: VF
authors: Van Tendeloo
authors: I Jolanda
authors: IJ
authors: de Vries
authors: Gosse J
authors: GJ
authors: Adema
authors: Zwi N
authors: ZN
authors: Berneman
authors: Evelien L J
authors: EL
authors: Smits
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D018274:Electroporation; D006801:Humans; D016219:Immunotherapy, Adoptive; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D012333:RNA, Messenger / Q000008:administration & dosage / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D016898:Interferon-alpha; D012333:RNA, Messenger; D025721:WT1 Proteins; C583751:WT1 protein, human