Burst release of encapsulated annexin A5 in tumours boosts cytotoxic T-cell responses by blocking the phagocytosis of apoptotic cells.

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.

• Authors: Ling Li, Jianhua Zou, Yunlu Dai, Wenpei Fan, Gang Niu, Zhen Yang, Xiaoyuan Chen
• Journal: Nature biomedical engineering (Nat Biomed Eng) Vol. 4 Issue 11 Pg. 1102-1116 (11 2020) ISSN: 2157-846X [Electronic] England
• PMID: 32807941 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Annexin A5
• Antineoplastic Agents
• Anxa5 protein, mouse

Topics

• Animals
• Annexin A5 (administration & dosage, chemistry, immunology)
• Antineoplastic Agents (administration & dosage, chemistry, immunology)
• Apoptosis (drug effects)
• Colorectal Neoplasms (immunology, therapy)
• Drug Delivery Systems (methods)
• Female
• Immunotherapy (methods)
• Melanoma (immunology, therapy)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neoplasms (immunology, therapy)
• Phagocytosis (drug effects)
• T-Lymphocytes (drug effects, immunology)