Nanogel-Based Immunologically Stealth Vaccine Targets Macrophages in the Medulla of Lymph Node and Induces Potent Antitumor Immunity

• Published in: ACS nano 2014-09, Vol.8 (9), p.9209-9218
• Main Authors: Muraoka, Daisuke, Harada, Naozumi, Hayashi, Tae, Tahara, Yoshiro, Momose, Fumiyasu, Sawada, Shin-ichi, Mukai, Sada-atsu, Akiyoshi, Kazunari, Shiku, Hiroshi
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antigens, Neoplasm - chemistry; Antigens, Neoplasm - immunology; Cancer Vaccines - chemistry; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cell Proliferation; Drug Carriers - chemistry; Female; Glucans - chemistry; Hydrogels - chemistry; Lymph Nodes - immunology; Macrophages - immunology; Mice; Molecular Sequence Data; Nanoparticles - chemistry; T-Lymphocytes - immunology; Toll-Like Receptors - agonists
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/nn502975r

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.