Engineered mitochondria exert potent antitumor immunity as a cancer vaccine platform  

作　　者：Jingwen Luo Fei Mo Zhe Zhang Weiqi Hong Tianxia Lan Yuan Cheng Chunju Fang Zhenfei Bi Furong Qin Jingyun Yang Ziqi Zhang Xue Li Haiying Que Jiayu Wang Siyuan Chen Yiming Wu Li Yang Jiong Li Wei Wang Chong Chen Xiawei Wei 

机构地区：[1]Laboratory of Aging Research and Cancer Drug Target,State Key Laboratory of Biotherapy and Cancer Center,National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University,Chengdu,Sichuan,China [2]Department of Medical Oncology,The First Affiliated Hospital of Kunming Medical University,Kunming,Yunnan,China [3]Zhejiang Provincial Key Laboratory of Pancreatic Disease,the First Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou,Zhejiang,China

出　　处：《Cellular & Molecular Immunology》2024年第11期1251-1265,共15页中国免疫学杂志(英文版)

基　　金：supported by the National Science Foundation for Excellent Young Scholars(32122052);National Natural Science Foundation Regional Innovation and Development(No.U19A2003);West China Hospital Postdoctoral Research and Development Fund(2023HXBH068);Guizhou Provincial Science and Technology Projects-ZK[2021]General 455.

摘　　要：The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency.Mitochondria,which feature prokaryotic characteristics and contain various damage-associated molecular patterns(DAMPs),are easily taken up by phagocytes and simultaneously activate innate immunity.In the current study,we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine.Ovalbumin(OVA)and tyrosinase-related protein 2(TRP2)were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides.The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2.Engineered OVA-and TRP2-containing mitochondria(OVA-MITO and TRP2-MITO)were extracted and evaluated as potential cancer vaccines.Impressively,the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models.Mechanistically,OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells(DCs)and induced a tumor-specific cell-mediated immunity.Moreover,DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist,namely,cardiolipin derived from the mitochondrial membrane.The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery,which could preferably target local dendritic cells and exert strong adaptive cellular immunity.This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases.

关 键 词：Mitochondria vaccine Antitumor immunity TLR2 CARDIOLIPIN 

分 类 号：R730.3[医药卫生—肿瘤]