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Enhancement of therapeutic DNA vaccine potency by melatonin through inhibiting VEGF expression and induction of antitumor immunity mediated by CD8+ T cells

Baghban Rahimi, S. and Mohebbi, A. and Vakilzadeh, G. and Biglari, P. and Razeghi Jahromi, S. and Mohebi, S.R. and Shirian, S. and Gorji, A. and Ghaemi, A. (2018) Enhancement of therapeutic DNA vaccine potency by melatonin through inhibiting VEGF expression and induction of antitumor immunity mediated by CD8+ T cells. Archives of Virology, 163 (3). pp. 587-597.

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Abstract

To be effective, therapeutic cancer vaccines should stimulate both an effective cell-mediated and a robust cytotoxic CD8+ T-cell response against human papillomavirus (HPV)-infected cells to treat the pre-existing tumors and prevent potential future tumors. In this study, the therapeutic experiments were designed in order to evaluate antitumor effect against the syngeneic TC-1 tumor model. The anti-tumor efficacy of a HPV-16 E7 DNA vaccine adjuvanted with melatonin (MLT) was evaluated in a C57BL/6 mouse tumor model by measuring tumor growth post vaccination and the survival rate of tumor-bearing mice, analyzing the specific lymphocyte proliferation responses in control and vaccinated mice by MTT assay. The E7-specific cytotoxic T cells (CTL) were analyzed by lymphocyte proliferation and lactate dehydrogenates (LDH) release assays. IFN-γ, IL-4 and TNF-α secretion in splenocyte cultures as well as vascular endothelial growth factor (VEGF) and IL-10 in the tumor microenvironment were assayed by ELISA. Our results demonstrated that subcutaneous administration of C57BL/6 mice with a DNA vaccine adjuvanted with MLT dose-dependently and significantly induced strong HPV16 E7-specific CD8+ cytotoxicity and IFN-γ and TNF-α responses capable of reducing HPV-16 E7-expressing tumor volume. A significantly higher level of E7-specific T-cell proliferation was also found in the adjuvanted vaccine group. Furthermore, tumor growth was significantly inhibited when the DNA vaccine was combined with MLT and the survival time of TC-1 tumor bearing mice was also significantly prolonged. In vivo studies further demonstrated that MLT decreased the accumulation of IL-10 and VEGF in the tumor microenvironment of vaccinated mice. These data indicate that melatonin as an adjuvant augmented the cancer vaccine efficiency against HPV-associated tumors in a dose dependent manner. © 2017, Springer-Verlag GmbH Austria, part of Springer Nature.

Item Type: Article
Additional Information: cited By 0
Uncontrolled Keywords: cancer vaccine; DNA vaccine; gamma interferon; immunological adjuvant; interleukin 4; melatonin; oncogene protein E7, Human papillomavirus type 16; protein E7; tumor necrosis factor; vascular endothelial growth factor A, mouse; vasculotropin A; Wart virus vaccine, administration and dosage; animal; antagonists and inhibitors; C57BL mouse; cell proliferation; chemistry; cytotoxic T lymphocyte; drug effects; epithelium cell; female; gene expression regulation; genetics; Human papillomavirus type 16; immunology; lymphocyte activation; mortality; mouse; papillomavirus infection; plasmid; survival analysis; tumor cell line; tumor volume; vaccination; virology, Adjuvants, Immunologic; Animals; Cancer Vaccines; Cell Line, Tumor; Cell Proliferation; Epithelial Cells; Female; Gene Expression Regulation; Human papillomavirus 16; Interferon-gamma; Interleukin-4; Lymphocyte Activation; Melatonin; Mice; Mice, Inbred C57BL; Papillomavirus E7 Proteins; Papillomavirus Infections; Papillomavirus Vaccines; Plasmids; Survival Analysis; T-Lymphocytes, Cytotoxic; Tumor Burden; Tumor Necrosis Factor-alpha; Vaccination; Vaccines, DNA; Vascular Endothelial Growth Factor A
Subjects: مقالات نمایه شده محققین دانشگاه در سایت ,Web of Science ,Scopus
Divisions: UNSPECIFIED
Depositing User: GOUMS
Date Deposited: 16 Apr 2018 05:21
Last Modified: 16 Apr 2018 05:21
URI: http://eprints.goums.ac.ir/id/eprint/9547

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