The transduction pattern of IL‐12‐encoding lentiviral vectors shapes the immunological outcome. Issue 12 (27th October 2015)

• Record Type: Journal Article
• Authors: Goyvaerts, Cleo; Broos, Katrijn; Escors, David; Heirman, Carlo; Raes, Geert; De Baetselier, Patrick; Thielemans, Kris; Breckpot, Karine
• Is Part Of: European journal of immunology. Volume 45:Issue 12(2015:Dec.)
• Page Start: 3351
• Page End: 3361
• Publication Date: 2015-10-27
• Subjects: Antigen‐presenting cell -- Cancer -- IL‐12 -- Immunotherapy -- Lentiviral vector -- Nanobody -- Targeting; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201545559
• Languages: English
• ISSNs: 0014-2980

Abstract

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 TH 1 profile is of minor importance for antitumor immunotherapy if IL‐12 is exogenously delivered.