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.

Natural compounds that regulate lymph node sinus macrophages: Inducing an anti-tumor effect by regulating macrophage activation

“…It was reported that cholesteryl pullulan (CHP) nanogels induce tumor regression in some patients with malignant tumors, 29,30 and CD169-positive macrophages in LN sinus captured CHP nanogels and worked as APCs. 31 Thus, lymphatic-targeting materials might be a promising approach to improving vaccine efficacy, and CD169-positive macrophages are now of interest as APCs to which antigens might be efficiently delivered.…”

Synthetic Nanoparticles for Vaccines and Immunotherapy

“…157 In comparison to soluble antigen formulated in Incomplete Freund’s Adjuvant, antigen encapsulated in these hydrogel nanoparticles substantially delayed tumor growth in a cancer therapeutic model. 157 …”

Sustained‐immunostimulatory nanocellulose scaffold to enhance vaccine efficacy

“…These targeted delivery processes enable less toxic and more effective vaccination by controlling drug dose and prolonging antibody immune responses (Hubbell, Thomas, & Swartz, ). Although nanomaterial‐based platforms using micelles (Cui, Osada, Imaizumi, Kataoka, & Nakano, ), liposomes (Demento et al, ; Yuba, Yamaguchi, Yoshizaki, Harada, & Kono, ), nanoparticles (Shima, Akagi, Uto, & Akashi, ; Uto et al, ), and nanogels (Muraoka et al, ; Nochi et al, ) have been successful, several nanomaterials lacks targeting ability to APCs due to the diffusion in the tissues after subcutaneous injection, which may lead to high total drug dose, multiple administration, and poor vaccine efficacy.…”