Self-adjuvanted nanovaccine for cancer immunotherapy: Role of lysosomal rupture-induced ROS in MHC class I antigen presentation

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• 作者：Ce Wang¹ ; Ping Li¹ ; Lanlan Liu ; Hong Pan ; Hongchang Li ; Lintao Cai ; Yifan Ma ; ^{yf.ma@siat.ac.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：pH-sensitive ; Lysosomal rupture ; ROS ; Proteasome activity ; MHC I antigen presentation
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：79
• 期：Complete
• 页码：88-100
• 全文大小：3408 K

文摘

MHC class I (MHC I) antigen presentation of exogenous antigens (so called “cross presentation”) is a central mechanism of CD8⁺ cytotoxic T lymphocyte (CTL) responses essential for successful vaccine-based cancer immunotherapy. The present study constructed amphiphilic pH-sensitive galactosyl dextran-retinal (GDR) nanogels for cancer vaccine delivery, in which dextran was conjugated with all-trans retinal (a metabolite of vitamin A) through a pH-sensitive hydrazone bond, followed by galactosylation to acquire dendritic cell (DC)-targeting ability. Our results showed that pH-sensitive GDR nanogel was a self-adjuvanted vaccine carrier that not only promoted DC maturation through activating retinoic acid receptor (RAR) signaling, but also facilitated antigen uptake and cytosolic antigen release in DCs. Furthermore, pH-sensitive GDR nanogel effectively augmented MHC I antigen presentation and evoked potent anti-cancer immune responses in vivo. More importantly, we first reported that nanoparticle-triggered lysosome rupture could directly induce ROS production in DCs, which was found to be essential for augmenting proteasome activity and downstream MHC I antigen presentation. Hence, DC-targeted pH-sensitive GDR nanogels could be a potent delivery system for cancer vaccine development. Triggering lyososomal rupture in DCs with pH-sensitive nanoparticles might be a plausible strategy to elevate intracellular ROS production for promoting antigen cross presentation, thereby improving cancer vaccine efficacy.