Journal
NATURE BIOMEDICAL ENGINEERING
Volume 4, Issue 11, Pages 1102-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41551-020-0599-5
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Funding
- Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health
- Faculty of Health Sciences, University of Macau
- University of Macau [SRG2018-00130-FHS]
- Science and Technology Development Fund (FDCT), Macao SAR [FDCT 0109/2018/A3]
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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. The burst release of annexin A5 from intravenously injected nanoparticles that rapidly degrade in tumours generates robust anti-tumour immunity by shifting late-stage immunosuppressive apoptosis to immunostimulatory necrosis.
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