Abstract
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.
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Data availability
The main data supporting the results in this study are available within the paper and its Supplementary Information. All data generated in this study, including source data and the data used to make the figures, are available from figshare with the identifier https://doi.org/10.6084/m9.figshare.12417110.v1.
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Acknowledgements
This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, the Faculty of Health Sciences, University of Macau, a Start-up Research Grant of the University of Macau (SRG2018-00130-FHS) and the Science and Technology Development Fund (FDCT), Macao SAR (FDCT 0109/2018/A3). We thank V. Schram for help with confocal microscopy imaging, Henry S. Eden for proof-reading the manuscript and Guangzhou Sagene Biotech for help with making the pattern diagrams.
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X.C., L.L., W.F. and Z.Y. conceived the study, designed the experiments and wrote the manuscript. L.L., J.Z., W.F. and Z.Y. performed the experiments and analysed data. Y.D. and G.N. re-evaluated the anti-tumour activity.
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Li, L., Zou, J., Dai, Y. et al. Burst release of encapsulated annexin A5 in tumours boosts cytotoxic T-cell responses by blocking the phagocytosis of apoptotic cells. Nat Biomed Eng 4, 1102–1116 (2020). https://doi.org/10.1038/s41551-020-0599-5
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DOI: https://doi.org/10.1038/s41551-020-0599-5
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