title: Induction of anti-tumor cytotoxic T cell responses through PLGA-nanoparticle mediated antigen delivery.
abstract: Nanotechnology-based antigen delivery has been developing as a vaccine strategy due to its dose-sparing and prolonged antigen presentation features. In the current study, we examined the feasibility of nanoparticle (NP)-mediated delivery of antigenic peptides to efficiently induce cytotoxic T lymphocyte responses against tumor-associated self-antigens in C57BL/6 mouse models. The biodegradable poly(D,L-lactide-co-glycolide) nanoparticle (PLGA-NP) carrying murine melanoma antigenic peptides, hgp100(25-33) and TRP2(180-188), were prepared by double emulsion method. Efficient uptake of PLGA-NP by murine dendritic cells was shown in vitro and in vivo, using NP labeled with the fluorescent dye DiD. Intradermal injection of peptide-loaded PLGA-NP into mice induced antigen-specific T cell responses more strongly than the peptides mixed with Freund's adjuvant. More importantly, vaccination with PLGA-NP carrying both TRP2(180-188) and a toll-like receptor 4 agonist, monophosphoryl lipid A, significantly delayed growth of subcutaneously inoculated B16 melanoma cells in a prophylactic setting. Furthermore, the anti-tumor activity of NP-mediated peptide vaccination was significantly augmented by combined treatment with interferon-γ, which might prevent tumor escape through up-regulation of MHC class I expression on tumor cells. Our findings demonstrate the feasibility of NP-mediated antigen delivery for cancer immunotherapy, in particular when immune escape mechanisms of tumor cells are blocked simultaneously.
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Songsak
authors.initials: S
authors.lastname: Tongchusak
authors.forename: Yo
authors.initials: Y
authors.lastname: Mizukami
authors.forename: Yoon Joong
authors.initials: YJ
authors.lastname: Kang
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ioji
authors.forename: Maki
authors.initials: M
authors.lastname: Touma
authors.forename: Bruce
authors.initials: B
authors.lastname: Reinhold
authors.forename: Derin B
authors.initials: DB
authors.lastname: Keskin
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sasada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000737:chemistry / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D019344:Lactic Acid / Q000737:chemistry*; D013058:Mass Spectrometry; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053719:Tandem Mass Spectrometry
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D010455:Peptides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid