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.
Department of Medical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
Cell Mol Immunol. 2024 Nov;21(11):1251-1265. doi: 10.1038/s41423-024-01203-4. Epub 2024 Aug 20.
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.
理想的抗原递呈谱伴随着足够的佐剂有利于疫苗的效率。线粒体具有原核特征，含有各种损伤相关分子模式（DAMPs），容易被吞噬细胞摄取，并同时激活先天免疫。在本研究中，我们建立了一个线粒体工程平台，用于生成富含抗原的线粒体作为癌症疫苗。卵清蛋白（OVA）和酪氨酸酶相关蛋白 2（TRP2）被用作模型抗原，与定位于线粒体的信号肽融合。然后采用慢病毒感染系统产生含有 OVA 或 TRP2 的线粒体疫苗。提取并评估了工程化的含有 OVA 和 TRP2 的线粒体（OVA-MITO 和 TRP2-MITO）作为潜在的癌症疫苗。令人印象深刻的是，当作为预防性和治疗性疫苗在小鼠肿瘤模型中使用时，工程化的线粒体疫苗显示出有效的抗肿瘤作用。从机制上讲，OVA-MITO 和 TRP2-MITO 能够有效地招募和激活树突状细胞（DC），并诱导肿瘤特异性细胞介导的免疫。此外，线粒体疫苗对 DC 的激活关键涉及 TLR2 途径及其脂质激动剂，即来自线粒体膜的心磷脂。结果表明，工程化的线粒体是天然的、精心协调的载体，充满了抗原递呈的免疫刺激物，可优先靶向局部树突状细胞，并发挥强大的适应性细胞免疫。这项概念验证研究为癌症以及其他疾病的工程化携带可改变抗原的线粒体疫苗构建建立了一个通用平台。
