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: Yannick Willemen, Johan M J Van den Bergh, Eva Lion, Sébastien Anguille, Vicky A E Roelandts, Heleen H Van Acker, Steven D I Heynderickx, Barbara M H Stein, Marc Peeters, Carl G Figdor, Viggo F I Van Tendeloo, I Jolanda de Vries, Gosse J Adema, Zwi N Berneman, Evelien L J Smits
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 64 Issue 7 Pg. 831-42 (Jul 2015) ISSN: 1432-0851 [Electronic] Germany
• PMID: 25863943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Interferon-alpha
• RNA, Messenger
• WT1 Proteins
• WT1 protein, human

Topics

• Antigens, Neoplasm (genetics, immunology)
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Proliferation (genetics)
• Cells, Cultured
• Dendritic Cells (cytology, immunology, transplantation)
• Electroporation
• Humans
• Immunotherapy, Adoptive
• Interferon-alpha (genetics, metabolism)
• Killer Cells, Natural (immunology)
• Lymphocyte Activation (immunology)
• Neoplasms (immunology)
• RNA, Messenger (administration & dosage, genetics)
• WT1 Proteins (genetics, immunology)