The Immunogenicity and Immunoprotection of VBP3 Multi-epitope Vaccine Targeting Angiogenesis and Tumor Inhibition in Lung Cancer-Bearing Mice
- 81 Downloads
The proangiogenic factors including basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) which work synergistically are essential for tumor angiogenesis and tumor growth. The bFGF/VEGF multi-epitope complex peptide (VBP3) was constructed with six different epitope peptides from human bFGF and VEGF. The VBP3 multi-epitope complex peptide was demonstrated good immunogenicity to elicit high titer anti-bFGF antibody and anti-VEGF antibody in C57BL/6 mice. In Lewis lung cancer (LLC) mouse model, the tumor growth was significantly inhibited which resulted in a longer survival time. The immunohistochemistry results showed that the tumor angiogenesis was inhibited with VBP3 vaccine vaccination. The results of flow cytometry (FCM) assay showed that the activation of dentritic cells (DC), CD4+ and CD8+ T cells were stimulated while the infiltration of myeloid-derived suppressor cells and macrophages were suppressed in tumor microenvironment. The polyclonal antibodies were separated from the VBP3-vaccinated mice. The CCK-8 assay results showed that the proliferation of LL-2 cancer cells was inhibited and the Western-blot assay results showed that the phosphorylation levels of Akt and Erk1/2 were decreased by the antibodies. The results indicated that the VBP3 could stimulate specific immune responses to inhibit tumor angiogenesis and tumor growth. The VBP3 with good immunogenicity and immunoprotection could be used as a potential therapeutic peptide vaccine for tumor therapy.
KeywordsbFGF/VEGF Tumor angiogenesis VBP3 multi-epitope complex peptide Immunogenicity Lung cancer bearing-mice Immunoprotection
This work was supported by the Grants from State Natural Science Foundation of China (81372281), Science and Technology Planning Project of Guangdong Province (2015B020211009, 2016A010105008) and Science and Technology Planning Project of Guangzhou City (201604020099).
Compliance with Ethical Standards
Conflict of interest
Ligang Zhang, Dan He, Jianhua Huang, Yanrui Deng, Ruiqiang Weng, Lei Pan, Ning Deng declared that they have no conflict of interest.
Human and Animal Participants
All international, national, and institutional guidelines for the care and use of laboratory animals were followed. This article did not involve any study with human participants.
Informed consent was obtained from all individual participants included in the study.
- Demirkesen C, BüyükpInarbasIlI N, Ramazanoglu R, Oguz O, Mandel NM et al (2006) The correlation of angiogenesis with metastasis in primary cutaneous melanoma: a comparative analysis of microvessel density, expression of vascular endothelial growth factor and basic fibroblastic growth factor. Pathology 38:132–137. https://doi.org/10.1080/00313020600557565 CrossRefGoogle Scholar
- Foy KC, Miller MJ, Moldovan N, Carson WE, Kaumaya PTP (2012) Combined vaccination with HER-2 peptide followed by therapy with VEGF peptide mimics exerts effective anti-tumor and anti-angiogenic effects in vitro and in vivo. OncoImmunology 1:1048–1060. https://doi.org/10.4161/onci.20708 CrossRefGoogle Scholar
- Gerber H-P, Ferrara N (2005) Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Can Res 65:671–680Google Scholar
- Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S et al (2007) Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 13:1367–1373. https://doi.org/10.1634/theoncologist.12-1-107 CrossRefGoogle Scholar
- Suzuki H, Fukuhara M, Yamaura T, Mutoh S, Okabe N et al (2013) Multiple therapeutic peptide vaccines consisting of combined novel cancer testis antigens and anti-angiogenic peptides for patients with non-small cell lung cancer. J Transl Med 11:97. https://doi.org/10.1186/1479-5876-11-97 CrossRefGoogle Scholar
- Tartour E, Pere H, Maillere B, Terme M, Merillon N et al (2011) Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of anti-angiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 30:83–95. https://doi.org/10.1007/s10555-011-9281-4 CrossRefGoogle Scholar
- Wang H, Zhu Z, Yang Q, Xiang J, Yang H et al (2010) Screening the antigen epitopes of bFGF/VEGF and expressing and identifying their complex peptide. Immunol J 26:688–693Google Scholar
- Zhou H, Luo Y, Mizutani M, Mizutani N, Dolman C et al (2004) A DNA minigene vaccine against VEGF receptor 2 (Flk-1) suppresses angiogenesis and successfully inhibits growth of prostate and lung carcinoma in mice. Can Res 64:326–326Google Scholar