title: Self-adjuvanted nanovaccine for cancer immunotherapy: Role of lysosomal rupture-induced ROS in MHC class I antigen presentation.
abstract: 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.
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Ce
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Pan
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Hongchang
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China.
authors.forename: Lintao
authors.initials: L
authors.lastname: Cai
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen 518055, PR China. Electronic address: yf.ma@siat.ac.cn.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage*; D002478:Cells, Cultured; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006863:Hydrogen-Ion Concentration; D007167:Immunotherapy / Q000379:methods; D008247:Lysosomes / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D017382:Reactive Oxygen Species / Q000276:immunology*; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D019496:Cancer Vaccines; D003692:Delayed-Action Preparations; D015395:Histocompatibility Antigens Class I; D053769:Nanocapsules; D017382:Reactive Oxygen Species
keywords: Lysosomal rupture; MHC I antigen presentation; Proteasome activity; ROS; pH-sensitive