title: Preclinical evaluation of TriMix and antigen mRNA-based antitumor therapy.
abstract: The use of tumor-associated antigen (TAA) mRNA for therapeutic purposes is under active investigation. To be effective, mRNA vaccines need to deliver activation stimuli in addition to TAAs to dendritic cells (DC). In this study, we evaluated whether intranodal delivery of TAA mRNA together with TriMix, a mix of mRNA encoding CD40 ligand, constitutive active Toll-like receptor 4 and CD70, results in the in situ modification and maturation of DCs, hence, priming of TAA-specific T cells. We showed selective uptake and translation of mRNA in vivo by lymph node resident CD11c(+) cells. This process was hampered by codelivery of classical maturation stimuli but not by TriMix mRNA. Importantly, TriMix mRNA induced a T-cell-attracting and stimulatory environment, including recruitment of antigen-specific CD4(+) and CD8(+) T cells and CTLs against various TAAs. In several mouse tumor models, mRNA vaccination was as efficient in CTL induction and therapy response as vaccination with mRNA-electroporated DCs. Together, our findings suggest that intranodal administration of TAA mRNA together with mRNA encoding immunomodulating molecules is a promising vaccination strategy.
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Jette, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Van Lint
authors.forename: Cleo
authors.initials: C
authors.lastname: Goyvaerts
authors.forename: Sarah
authors.initials: S
authors.lastname: Maenhout
authors.forename: Lode
authors.initials: L
authors.lastname: Goethals
authors.forename: Aurélie
authors.initials: A
authors.lastname: Disy
authors.forename: Daphné
authors.initials: D
authors.lastname: Benteyn
authors.forename: Joeri
authors.initials: J
authors.lastname: Pen
authors.forename: Aude
authors.initials: A
authors.lastname: Bonehill
authors.forename: Carlo
authors.initials: C
authors.lastname: Heirman
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D039521:CD11c Antigen / Q000032:analysis; D053282:CD27 Ligand / Q000235:genetics*; D023201:CD40 Ligand / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology; D053672:Electrochemotherapy; D005260:Female; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D012333:RNA, Messenger / Q000276:immunology* / Q000493:pharmacokinetics; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014611:Vaccination
chemical_list: D000951:Antigens, Neoplasm; D039521:CD11c Antigen; D053282:CD27 Ligand; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D023201:CD40 Ligand