Antigen degradation during acidification associated with endosomal maturation reduces the capacity of DCs to cross-present. Bikorimana et al. showed that DC uptake of OVA conjugated to an Accum moiety (aOVA) leads to rupture of endosomal membranes, enhanced proteasome processing, and potentiation of T cell activation. In the OVA-expressing EG.7 model, beneficial antitumor responses were observed with prophylactic immunization with aOVA protein and with aOVA-pulsed DCs. Therapeutic immunization with either aOVA-pulsed DC or tumor lysate-pulsed DCs was also efficacious, and improved with anti-PD-1 therapy.
Contributed by Margot O’Toole
ABSTRACT: The cross-presenting capacity of dendritic cells (DCs) can be limited by non-specific degradation during endosome maturation. To bypass this limitation, we present in this study a new Accum-based formulation designed to promote endosome-to-cytosol escape. Treatment of primary DCs with Accum linked to the xenoantigen ovalbumin (OVA) triggers endosomal damages and enhances protein processing. Despite multiple challenges using ascending doses of tumor cells, DC prophylactic vaccination results in complete protection due to increased levels of effector CD4 and CD8 T cells as well as high production of pro-inflammatory mediators. When combined with anti-PD-1, therapeutic vaccination using both syngeneic and allogeneic Accum-OVA-pulsed DCs triggers potent anti-tumoral responses. The net outcome culminates in increased CD11c, CD8, and NK infiltration along with a high CD8/Treg ratio. These highly favorable therapeutic effects highlight the promising potential of Accum as a distinct and potent technology platform suitable for the design of next generation cell cancer vaccines.
Author Info: (1) Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC, Canada; (2) Department of Biomedical Sciences, Université de Montréal, Montréal,
Author Info: (1) Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC, Canada; (2) Department of Biomedical Sciences, Université de Montréal, Montréal, QC, Canada; (3) Research and Development Branch, Defence Therapeutics Inc., Vancouver, BC, Canada; (4) Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC, Canada; (5) Department of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; (6) Molecular Biology Program, Université de Montréal, Montréal, QC, Canada
