title: Intratumoral administration of mRNA encoding a fusokine consisting of IFN-β and the ectodomain of the TGF-β receptor II potentiates antitumor immunity.
abstract: It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8⁺ cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-β and the ectodomain of the transforming growth factor-β receptor II, referred to as Fβ², showed therapeutic potential. The treatment efficacy was dependent on CD8⁺ T cells and could be improved through blockade of PD-1/PD-L1 interactions. In vitro studies revealed that administration of Fβ² to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fβ² enhanced the antigen presenting capacity of dendritic cells, whilst reducing the suppressive activity of myeloid-derived suppressor cells. In conclusion, these data suggest that intratumoral delivery of mRNA encoding soluble proteins, such as Fβ², can modulate the tumor microenvironment, leading to effective antitumor T cell responses, which can be further potentiated through combination therapy.
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Kevin
authors.initials: K
authors.lastname: Van der Jeught
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Patrick Tjok
authors.initials: PT
authors.lastname: Joe
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Bialkowski
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Carlo
authors.initials: C
authors.lastname: Heirman
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Lidia
authors.initials: L
authors.lastname: Daszkiewicz
authors.affiliation: Rayne Institute, University College London, London, UK.
authors.forename: Therese
authors.initials: T
authors.lastname: Liechtenstein
authors.affiliation: Rayne Institute, University College London, London, UK. Biomedical Research Centre NavarraBiomed-Fundacion Miguel Servet, National Health Service of Navarre, Pamplona, Navarre, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Escors
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D015552:Injections, Intralesional; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II