title: Nanogel-based immunologically stealth vaccine targets macrophages in the medulla of lymph node and induces potent antitumor immunity.
abstract: Because existing therapeutic cancer vaccines provide only a limited clinical benefit, a different vaccination strategy is necessary to improve vaccine efficacy. We developed a nanoparticulate cancer vaccine by encapsulating a synthetic long peptide antigen within an immunologically inert nanoparticulate hydrogel (nanogel) of cholesteryl pullulan (CHP). After subcutaneous injection to mice, the nanogel-based vaccine was efficiently transported to the draining lymph node, and was preferentially engulfed by medullary macrophages but was not sensed by other macrophages and dendritic cells (so-called "immunologically stealth mode"). Although the function of medullary macrophages in T cell immunity has been unexplored so far, these macrophages effectively cross-primed the vaccine-specific CD8(+) T cells in the presence of a Toll-like receptor (TLR) agonist as an adjuvant. The nanogel-based vaccine significantly inhibited in vivo tumor growth in the prophylactic and therapeutic settings, compared to another vaccine formulation using a conventional delivery system, incomplete Freund's adjuvant. We also revealed that lymph node macrophages were highly responsive to TLR stimulation, which may underlie the potency of the macrophage-oriented, nanogel-based vaccine. These results indicate that targeting medullary macrophages using the immunologically stealth nanoparticulate delivery system is an effective vaccine strategy.
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine , Mie 514-8507, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Muraoka
authors.forename: Naozumi
authors.initials: N
authors.lastname: Harada
authors.forename: Tae
authors.initials: T
authors.lastname: Hayashi
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Tahara
authors.forename: Fumiyasu
authors.initials: F
authors.lastname: Momose
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Sawada
authors.forename: Sada-atsu
authors.initials: SA
authors.lastname: Mukai
authors.forename: Kazunari
authors.initials: K
authors.lastname: Akiyoshi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000737:chemistry / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D005936:Glucans / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry*; D008198:Lymph Nodes / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry*; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004337:Drug Carriers; D005936:Glucans; D020100:Hydrogels; D051193:Toll-Like Receptors; C009109:pullulan
keywords: T cells; cancer vaccine; lymph node; macrophages; nanogel; vaccine delivery