Abstract
AIMS: Despite the existence of effective preventive vaccines for human papillomavirus (HPV), therapeutic vaccines that trigger cell-mediated immune responses are required to treat established infections and malignancies. The aim of this study was to evaluate the therapeutic potency of HPV-16 E7 deoxyribonucleic acid (DNA) vaccine alone and with interleukin (IL)-18. METHODS: In vitro expressions of IL-18 were performed on human embryonic kidney 293 cells and confirmed it by Western blotting methods. DNA vaccine was available from a previous study. A total of 45 female C57BL/6 mice divided into five groups (DNA vaccine, DNA vaccine adjuvanted with IL-18, pcDNA3.1, and phosphate buffer saline) were inoculated with murine tissue culture-1 cell line of HPV related carcinoma, expressing HPV-16 E6/E7 antigens. They were then immunized subcutaneously twice at a seven-day interval. The antitumor and antigen specific-cellular immunity were assessed by lymphocyte proliferation (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide: MTT) assay, lactate dehydrogenase release assay, IL-4 assay and interferon-gamma (IFN-γ) assay. Tumor size was followed for 62 days.RESULTS: MTT assay, which measures the lymphocyte proliferation in response to the specific antigen, increased in the co-administration and the DNA vaccine groups as compared to control and genetic adjuvant groups (p<0.001). The mice immunized with the co-administration generated significantly more IFN-γ and IL-4 than other immunized mice (p<0.001). Reduction of the tumor size in the co-administration and the DNA vaccine groups was significantly more pronounced than in the control and genetic adjuvant groups (p<0.001), but no statistically significant difference between DNA vaccine and co-administration groups (p=0.15) occurred.CONCLUSIONS: IL-18 as a genetic adjuvant and E7 DNA vaccine alone enhanced immune responses in mouse model systems against cervical cancer. However, using of IL-18 as a genetic adjuvant with E7 DNA vaccine had no significant synergistic effect on the immune responses in vivo.
Highlights
Cervical cancer is the fourth most common cause of cancer and deaths among women worldwide
A total of 45 female C57BL/6 mice divided into five groups (DNA vaccine, deoxyribonucleic acid (DNA) vaccine adjuvanted with IL-18, pcDNA3.1, and phosphate buffer saline) were inoculated with murine tissue culture-1 cell line of human papillomavirus (HPV) related carcinoma, expressing HPV-16 E6/Early 7 (E7) antigens
Mouse recombinant IL-18 cloned in pcDNA3.1 as a genetic adjuvant was purchased from BioMatik (Waltham, MA, USA) and the recombinant DNA vaccine was obtained from our previous study [17]
Summary
Cervical cancer is the fourth most common cause of cancer and deaths among women worldwide. In HPV-associated cervical cancers, the viral deoxyribonucleic acid (DNA) integration into the host genome causes an upregulation of HPV oncogenes (E6 and E7) which disrupts the cell cycle and interferes with apoptosis [3]. The E7 oncoprotein can bind to the hypophosphorylated form of the retinoblastoma protein and degrade it. Degradation of this retinoblastoma phosphoprotein, Rb, is leaded to release repression of the E2F transcription factor and allows cells to progress through G1 into S phase [4,5,6]. HPV-16 E7 can induce apoptosis in the absence of E6 that is associated with nuclear breakdown [6]
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