Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD, USA.
Faculty of Health Sciences, University of Macau, Macau, P. R. China.
Nat Biomed Eng. 2020 Nov;4(11):1102-1116. doi: 10.1038/s41551-020-0599-5. Epub 2020 Aug 17.
Cancer immunotherapies, particularly therapeutic vaccination, do not typically generate robust anti-tumour immune responses. Here, we show that the intratumoral burst release of the protein annexin A5 from intravenously injected hollow mesoporous nanoparticles made of diselenide-bridged organosilica generates robust anti-tumour immunity by exploiting the capacity of primary tumours to act as antigen depots. Annexin A5 blocks immunosuppressive apoptosis and promotes immunostimulatory secondary necrosis by binding to the phagocytic marker phosphatidylserine on dying tumour cells. In mice bearing large established tumours, the burst release of annexin A5 owing to diselenide-bond cleavage under the oxidizing conditions of the tumour microenvironment and the reducing intracellular conditions of tumour cells induced systemic cytotoxic T-cell responses and immunological memory associated with tumour regression and the prevention of relapse, and led to complete tumour eradication in about 50% of mice with orthotopic breast tumours. Reducing apoptosis signalling via in situ vaccination could be a versatile strategy for the generation of adaptive anti-tumour immune responses.
癌症免疫疗法，特别是治疗性疫苗接种，通常不会产生强大的抗肿瘤免疫反应。在这里，我们表明，从静脉注射的由二硒键桥连有机硅烷制成的中空介孔纳米粒子中，蛋白 annexin A5 的肿瘤内爆发释放利用原发肿瘤作为抗原储存库的能力产生强大的抗肿瘤免疫。 Annexin A5 通过与死亡肿瘤细胞上的吞噬标记物磷脂酰丝氨酸结合，阻止免疫抑制性细胞凋亡并促进免疫刺激性继发性坏死。在患有大的已建立肿瘤的小鼠中，由于肿瘤微环境中的氧化条件和肿瘤细胞内的还原条件下二硒键的断裂，annexin A5 的爆发释放诱导了全身性细胞毒性 T 细胞反应和与肿瘤消退以及防止复发相关的免疫记忆，并导致约 50%的荷原位乳腺癌小鼠完全消除肿瘤。通过原位疫苗接种减少细胞凋亡信号可能是产生适应性抗肿瘤免疫反应的一种通用策略。
