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

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• 作者：Daisuke Muraoka ; Naozumi Harada ; Tae Hayashi ; Yoshiro Tahara ; Fumiyasu Momose ; Shin-ichi Sawada ; Sada-atsu Mukai ; Kazunari Akiyoshi ; Hiroshi Shiku
• 刊名：ACS Nano
• 出版年：2014
• 出版时间：September 23, 2014
• 年：2014
• 卷：8
• 期：9
• 页码：9209-9218
• 全文大小：628K
• ISSN：1936-086X

文摘

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 鈥渋mmunologically stealth mode鈥?. 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鈥檚 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.

Keywords:

cancer vaccine; nanogel; vaccine delivery; macrophages; lymph node; T cells