title: FLT3 ligand enhances the cancer therapeutic potency of naked RNA vaccines.
abstract: Intranodal immunization with antigen-encoding naked RNA may offer a simple and safe approach to induce antitumor immunity. RNA taken up by nodal dendritic cells (DC) coactivates toll-like receptor (TLR) signaling that will prime and expand antigen-specific T cells. In this study, we show that RNA vaccination can be optimized by coadministration of the DC-activating Fms-like tyrosine kinase 3 (FLT3) ligand as an effective adjuvant. Systemic administration of FLT3 ligand prior to immunization enhanced priming and expansion of antigen-specific CD8(+) T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodal RNA. Unexpectedly, plasmacytoid DCs (pDC) were found to be essential for the adjuvant effect of FLT3 ligand and they were systemically expanded together with conventional DCs after treatment. In response to FLT3 ligand, pDCs maintained an immature phenotype, internalized RNA, and presented the RNA-encoded antigen for efficient induction of antigen-specific CD8(+) T-cell responses. Coadministration of FLT3 ligand with RNA vaccination achieved remarkable cure rates and survival of mice with advanced melanoma. Our findings show how to improve the simple and safe strategy offered by RNA vaccines for cancer immunotherapy.
authors.affiliation: Institute for Translational Oncology and Immunology, Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kreiter
authors.forename: Mustafa
authors.initials: M
authors.lastname: Diken
authors.forename: Abderraouf
authors.initials: A
authors.lastname: Selmi
authors.forename: Jan
authors.initials: J
authors.lastname: Diekmann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Attig
authors.forename: Yves
authors.initials: Y
authors.lastname: Hüsemann
authors.forename: Michael
authors.initials: M
authors.lastname: Koslowski
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Türeci
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D009368:Neoplasm Transplantation; D012313:RNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D008565:Membrane Proteins; C084881:flt3 ligand protein; D012313:RNA