期刊
INTERNATIONAL JOURNAL OF NANOMEDICINE
卷 12, 期 -, 页码 6813-6825出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/IJN.S143264
关键词
outer membrane vesicles; dendritic cells; HPV immunotherapy
资金
- CAMS Initiative for Innovative Medicine [2016-I2M-1-019]
- Science and Technology Project of Yunnan Province [2016FA049]
- Fundamental Research Funds for the Central Universities of China [2012N08, 3332015197, 3332016117, 2016ZX350073]
- National Natural Science Foundation of China [81773270, 81573206]
- Fundamental Research Funds for Institute of Pathogen Biology of PUMC [2014IPB107]
- Peking Union Medical College (PUMC) Postgraduates Innovative Funds Project [10023-0710-1003]
Purpose: Currently, therapeutic tumor vaccines under development generally lack significant effects in human clinical trials. Exploring a powerful antigen delivery system is a potential approach to improve vaccine efficacy. We sought to explore engineered bacterial outer membrane vesicles (OMVs) as a new vaccine carrier for efficiently delivering tumor antigens and provoking robust antitumor immune responses. Materials and methods: First, the tumoral antigen human papillomavirus type 16 early protein E7 (HPV16E7) was presented on Escherichia coli-derived OMVs by genetic engineering methods, acquiring the recombinant OMV vaccine. Second, the ability of recombinant OMVs delivering their components and the model antigen green fluorescent protein to antigen-presenting cells was investigated in the macrophage Raw264.7 cells and in bone marrow-derived dendritic cells in vitro. Third, it was evaluated in TC-1 graft tumor model in mice that the recombinant OMVs displaying HPV16E7 stimulated specific cellular immune response and intervened the growth of established tumor. Results: E. coli DH5 alpha-derived OMVs could be taken up rapidly by dendritic cells, for which vesicle structure has been proven to be important. OMVs significantly stimulated the expression of dendritic cellmaturation markers CD80, CD86, CD83 and CD40. The HPV16E7 was successfully embedded in engineered OMVs through gene recombinant techniques. Subcutaneous immunization with the engineered OMVs induced E7 antigen-specific cellular immune responses, as shown by the increased numbers of interferon-gamma-expressing splenocytes by enzyme-linked immunospot assay and interferon-gamma-expressing CD4(+) and CD8(+) cells by flow cytometry analyses. Furthermore, the growth of grafted TC-1 tumors in mice was significantly suppressed by therapeutic vaccination. The recombinant E7 proteins presented by OMVs were more potent than those mixed with wild-type OMVs or administered alone for inducing specific cellular immunity and suppressing tumor growth. Conclusion: The results indicated that the nano-grade OMVs might be a useful vaccine platform for antigen delivery in cancer immunotherapy.
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