title: The transduction pattern of IL-12-encoding lentiviral vectors shapes the immunological outcome.
abstract: In situ modification of antigen-presenting cells garnered interest in cancer immunotherapy. Therefore, we developed APC-targeted lentiviral vectors (LVs). Unexpectedly, these LVs were inferior vaccines to broad tropism LVs. Since IL-12 is a potent mediator of antitumor immunity, we evaluated whether this proinflammatory cytokine could enhance antitumor immunity of an APC-targeted LV-based vaccine. Therefore, we compared subcutaneous administration of broad tropism LVs (VSV-G-LV) with APC-targeted LVs (DC2.1-LV)-encoding enhanced GFP and ovalbumin, or IL-12 and ovalbumin in mice. We show that codelivery of IL-12 by VSV-G-LVs or DC2.1-LVs augments CD4(+) or CD8(+) T-cell proliferation, respectively. Furthermore, we demonstrate that codelivery of IL-12 enhances the CD4(+) TH 1 profile irrespective of its delivery mode, while an increase in cytotoxic and therapeutic CD8(+) T cells was only induced upon VSV-G-LV injection. While codelivery of IL-12 by DC2.1-LVs did not enhance CD8(+) T-cell performance, it increased expression of inhibitory checkpoint markers Lag3, Tim3, and PD-1. Finally, the discrepancy between CD4(+) T-cell stimulation with and without functional CD8(+) T-cell stimulation by VSV-G- and DC2.1-LVs is partly explained by the observation that IL-12 relieves CD8(+) T cells from CD4(+) T-cell help, implying that a T(H)1 profile is of minor importance for antitumor immunotherapy if IL-12 is exogenously delivered.
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Cleo
authors.initials: C
authors.lastname: Goyvaerts
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Katrijn
authors.initials: K
authors.lastname: Broos
authors.affiliation: Navarrabiomed-Fundación Miguel Servet, Complejo Hospitalario de Navarra, Pamplona, 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: Carlo
authors.initials: C
authors.lastname: Heirman
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.|VIB Laboratory of Myeloid Cell Immunology, Brussels, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Raes
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.|VIB Laboratory of Myeloid Cell Immunology, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: De Baetselier
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; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D014161:Transduction, Genetic; D014759:Viral Envelope Proteins / Q000235:genetics
chemical_list: C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; D018664:Interleukin-12
keywords: Antigen-presenting cell; Cancer; IL-12; Immunotherapy; Lentiviral vector; Nanobody; Targeting