title: Co-delivery of PLGA encapsulated invariant NKT cell agonist with antigenic protein induce strong T cell-mediated antitumor immune responses.
abstract: Antitumor immunity can be enhanced by the coordinated release and delivery of antigens and immune-stimulating agents to antigen-presenting cells via biodegradable vaccine carriers. So far, encapsulation of TLR ligands and tumor-associated antigens augmented cytotoxic T cell (CTLs) responses. Here, we compared the efficacy of the invariant NKT (iNKT) cell agonist α-galactosylceramide (α-GalCer) and TLR ligands (R848 and poly I:C) as an adjuvant for the full length ovalbumin (OVA) in PLGA nanoparticles. We observed that OVA+α-GalCer nanoparticles (NP) are superior over OVA+TLR-L NP in generating and stimulating antigen-specific cytotoxic T lymphocytes without the need for CD4+T cell help. Not only a 4-fold higher induction of antigen-specific T cells was observed, but also a more profound IFN-γ secretion was obtained by the addition α-GalCer. Surprisingly, we observed that mixtures of OVA containing NP with α-GalCer were ineffective, demonstrating that co-encapsulation of both α-GalCer and antigen within the same nanoparticle is essential for the observed T cell responses. Moreover, a single immunization with OVA+α-GalCer NP provided substantial protection from tumor formation and even delayed the growth of already established tumors, which coincided with a prominent and enhanced antigen-specific CD8+T cell infiltration. The provided evidence on the advantage of antigen and α-GalCer coencapsulation should be considered in the design of future nanoparticle vaccines for therapeutic purposes.
authors.affiliation: Department of Tumor Immunology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Dölen
authors.affiliation: Department of Tumor Immunology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Kreutz
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford , Oxford, United Kingdom.
authors.forename: Uzi
authors.initials: U
authors.lastname: Gileadi
authors.affiliation: Department of Tumor Immunology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands.
authors.forename: Jurjen
authors.initials: J
authors.lastname: Tel
authors.affiliation: Department of Tumor Immunology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Vasaturo
authors.affiliation: Department of Tumor Immunology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands.
authors.forename: Eric A W
authors.initials: EA
authors.lastname: van Dinther
authors.affiliation: Department of Tumor Immunology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands.
authors.forename: Maaike A
authors.initials: MA
authors.lastname: van Hout-Kuijer
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford , Oxford, United Kingdom.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
authors.affiliation: Department of Tumor Immunology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
keywords: CTL response; PLGA; melanoma; nanoparticle; α-GalCer