title: Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells.
abstract: Modulating the activity of tumor-infiltrating dendritic cells (TiDC) provides opportunities for novel cancer interventions. In this article, we report on our study of the uptake of mRNA by CD8α(+) cross-presenting TiDCs upon its intratumoral (i.t.) delivery. We exploited this property to deliver mRNA encoding the costimulatory molecule CD70, the activation stimuli CD40 ligand, and constitutively active Toll-like receptor 4, referred to as TriMix mRNA. We show that TiDCs are reprogrammed to mature antigen-presenting cells that migrate to tumor-draining lymph nodes (TDLN). TriMix stimulated antitumor T-cell responses to spontaneously engulfed cancer antigens, including a neoepitope. We show in various mouse cancer models that i.t. delivery of TriMix mRNA results in systemic therapeutic antitumor immunity. Finally, we show that the induction of antitumor responses critically depends on TiDCs, whereas it only partially depends on TDLNs. As such, we provide a platform and a mechanistic rationale for the clinical testing of i.t. administration of TriMix mRNA.
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Van Lint
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium.
authors.forename: Dries
authors.initials: D
authors.lastname: Renmans
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium.
authors.forename: Katrijn
authors.initials: K
authors.lastname: Broos
authors.affiliation: In Vivo Cellular and Molecular Imaging Laboratory, VUB, Jette, Belgium.
authors.forename: Lode
authors.initials: L
authors.lastname: Goethals
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Maenhout
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium.
authors.forename: Daphné
authors.initials: D
authors.lastname: Benteyn
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium.
authors.forename: Cleo
authors.initials: C
authors.lastname: Goyvaerts
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Du Four
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium.
authors.forename: Kevin
authors.initials: K
authors.lastname: Van der Jeught
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Bialkowski
authors.affiliation: Institut d'Immunologie Médicale, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Flamand
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium.
authors.forename: Carlo
authors.initials: C
authors.lastname: Heirman
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium. kbreckpo@vub.ac.be kris.thielemans@vub.ac.be.
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.affiliation: Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel (VUB), Jette, Belgium. kbreckpo@vub.ac.be kris.thielemans@vub.ac.be.
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
mesh_terms: D000818:Animals; D015415:Biomarkers; D053282:CD27 Ligand / Q000235:genetics; D023201:CD40 Ligand / Q000235:genetics; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008213:Lymphocyte Activation; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000008:administration & dosage / Q000235:genetics*; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D015415:Biomarkers; D053282:CD27 Ligand; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D023201:CD40 Ligand