DNA vaccination against the ovarian carcinoma-associated antigen folate receptor α (FRα) induces cytotoxic T lymphocyte and antibody responses in mice

Neglia, Francesca; Orengo, Anna Maria; Cilli, Michele; Meazza, Raffaella; Tomassetti, Antonella; Canevari, Silvana; Melani, Cecilia; Colombo, Mario P.; Ferrini, Silvano

doi:10.1038/sj.cgt.7700053

Cited by 16 publications

(10 citation statements)

References 26 publications

(34 reference statements)

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“…DNA-based immunization can induce strong cellular immune responses to a variety of antigens, including tumor antigens, such as antigens associated with malignant melanoma [9][10][11] , ovarian carcinoma [12] , breast cancer [13,14] , smallcell lung cancer [15] , neuroblastoma [16] and prostate carcinoma [17] . Two major obstacles in developing rational strategies in tumor immunotherapy are identification of suitable target tumor antigens and effective process and presentation by professional antigen-presenting cells to induce T cell immunity.…”

Section: Introductionmentioning

confidence: 99%

Antitumor immunopreventive effect in mice induced by DNA vaccine encoding a fusion protein of -fetoprotein and CTLA4

Geng¹,

Yi²,

Xiong³

2004

WJG

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AIM:To develop a tumor DNA vaccine encoding a fusion protein of murine AFP and CTLA4, and to study its ability to induce specific CTL response and its protective effect against AFP-producing tumor. METHODS:Murine α-fetoprotein (mAFP) gene was cloned from total RNA of Hepa1-6 cells by RT-PCR. A DNA vaccine was constructed by fusion murine α-fetoprotein gene and extramembrane domain of murine CTLA4 gene. The DNA vaccine was identified by restriction enzyme analysis, sequencing and expression. EL-4 (mAFP) was developed by stable transfection of EL-4 cells with pmAFP. The frequency of cells producing IFN-γ in splenocytes harvested from the immunized mice was measured by ELISPOT. Mice immunized with DNA vaccine were inoculated with EL-4 (mAFP) cells in back to observe the protective effect of immunization on tumor. On the other hand, blood samples were collected from the immunized mice to check the functions of liver and kidney.RESULTS: 1.8 kb mAFP cDNA was cloned from total RNA of Hepa1-6 cells by RT-PCR. The DNA vaccine encoding a fusion protein of mAFP-CTLA4 was constructed and confirmed by restriction enzyme analysis, sequencing and expression. The expression of mAFP mRNA in EL-4 (mAFP) was confirmed by RT-PCR. The ELISPOT results showed that the number of IFN-γ-producing cells in pmAFP-CTLA4 group was significantly higher than that in pmAFP, pcDNA3.1 and PBS group. The tumor volume in pmAFP-CTLA4 group was significantly smaller than that in pmAFP, pcDNA3.1 and PBS group, respectively. The hepatic and kidney functions in each group were not altered.CONCLUSION: AFP-CTLA4 DNA vaccine can stimulate potent specific CTL responses and has distinctive antitumor effect on AFP-producing tumor. The vaccine has no impact on the function of mouse liver and kidney.Tian G, Yi JL, Xiong P. Antitumor immunopreventive effect in mice induced by DNA vaccine encoding a fusion protein of α-fetoprotein and CTLA4.

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Section: Introductionmentioning

confidence: 99%

Antitumor immunopreventive effect in mice induced by DNA vaccine encoding a fusion protein of -fetoprotein and CTLA4

Geng¹,

Yi²,

Xiong³

2004

WJG

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“…However, the questions of whether vaccine- and we therefore turned to a different form of in vivo neu-mimicking immunogen based on the discovery that inoculation of plasmid DNA can induce specific and long-lasting immunity in vivo in a variety of ag. [17][18][19][20][21][22][23][24][25][26] To break immune tolerance against rat neu in N#202 mice and to address the issue of host tolerance to naturally expressed tumor ag, we constructed a plasmid DNA vector encoding the full-length cDNA for the human HER-2/neu proto-oncogene (VR1012/HER-2) driven by the cytomegalovirus (CMV) early promoter/ enhancer and used it as immunogen since immunization against heterologous proteins can induce immune reactions against the corresponding 'self' antigen, through shared epitopes. For example, DNA vaccination against human melanoma antigen GP100 has been shown to induce cross-reactive CTL responses against the murine homologue of GP100.…”

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confidence: 99%

Prevention of spontaneous neu-expressing mammary tumor development in mice transgenic for rat proto-neu by DNA vaccination

et al. 2001

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The HER-2/neu proto-oncogene is overexpressed in 20-30% of human breast cancers and is associated with high recurrence risk. The oncogenic potential of HER-2/neu, together with its elevated expression in tumors, cell surface localization, and immunogenicity in some patients, make this oncoprotein an ideal target for immunotherapeutic approaches. To test the efficacy of immune-based strategies in eliciting an antitumor response, we used the N#202 transgenic mouse model engineered to overexpress the rat neu proto-oncogene under the control of the mouse mammary tumor virus promoter; females of this line develop spontaneous focal mammary tumors by 6 months of age. Transgenic mice immunized intramuscularly with a HER-2 cDNA ligated into the VR1012 (VICAL) expression vector under the control of the cytomegalovirus promoter developed signifiKeywords: DNA vaccination; proto-neu-transgenic mice; breast cancer Genetic alterations of human HER-2/neu proto-oncogene occur in 20-30% of breast cancers, and overexpression of the oncoprotein induces cell transformation and correlates with poor clinical outcome.1 HER-2/neu is a 'self' tumor antigen (ag) that is considered as an attractive target for immunotherapeutic intervention in light of its involvement in tumor aggressiveness, low-level expression in normal adult tissues and high-level expression in various malignancies, its cell surface localization and its native immunogenicity in humans. Indeed, some tumor patients develop specific antibody 2,3 and cellular 4,5 immune responses to HER-2/neu oncoprotein. In the rat model, anti-HER-2/neu vaccines were shown to induce and boost both B and T cell immunity. 6 Vaccine strategies directed against HER-2/neu and other self tumor ag must incorporate methods to overcome immunological tolerance to self proteins. cantly fewer spontaneous tumors as compared with mice injected with the empty vector (P Ͻ 0.0001) or not injected (P = 0.0006). However, this protection was observed only when immunization was started in 3-month-old but not in 6-month-old mice. These data suggest that the xenogeneic HER-2 DNA sequence can break immune tolerance to rat neu in transgenic N#202 mice and induce protective immunity that impairs the neu oncogene-driven progression of mammary carcinogenesis. The preventive effect achieved by our immunological approach appeared not to be based on anti-neu specific B and T cell immune attacks but was more possibly based on different mechanisms including aspecific and inflammatory immunological responses. Gene Therapy (2001) 8, 75-79. use of rat neu as immunogen and FVB mice transgenically expressing proto-neu 8,9 or mutated neu 10 as host. Different plasmid DNA constructs encoding mutated or wild-type human and rat HER-2/neu full-length or deleted genes in Balb/c and FVB mice transgenic for the mutated neu gene 11 have also been used. 12,13 Because parental FVB or Balb/c mice are not tolerant to rat neu or because of the possible immunogenicity of the mutated neu gene, these models might not be representative of th...

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“…It was reported that FRα-transduced C26 cells gradually lost FRα expression and the remaining tumor cells without FRα expression were not attacked by FRα specific immune reactivity (33). Therefore, the tumor growth showed similar growth kinetics with the control group at a later stage.…”

Section: Discussionmentioning

confidence: 80%

CpG oligodeoxynucleotides augment antitumor efficacy of folate receptor α based DNA vaccine

et al. 2017

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Abstract. Folate receptor α (FRα) is overexpressed in a variety of solid tumors and has become an attractive target antigen for immunotherapy purposes. A DNA vaccine was generated by ligation of FRα cDNA into the eukaryotic vector pcDNA3.1. Expression of FRα was confirmed in transiently transfected B16 cells. B16 cell lines that stably express FRα were set up by G418 selection. A total of 100 µg purified plasmid DNA alone or in combination with CpG oligodeoxynucleotides (CpG ODN) was injected intramuscularly in C57BL/6 mice four times at one week intervals. ELISA analysis confirmed that high titers of antibodies against FRα existed in the sera of the experimental animals. Specific cytotoxic T lymphocyte activity against FRα-expressing B16 cells was found and FRα specific lymphocyte proliferation was detected. Coinjection of CpG ODN increased both humoral and cellular immune responses. In the protective model, in which C57BL/6 mice were immunized with the FRα DNA vaccine four weeks before tumor cell inoculation, the growth of tumor was significantly inhibited, and the presence of CpG ODN further increased the inhibitory effect. FRα DNA vaccine alone did not show a significant inhibitory effect in the therapeutic model, in which the DNA vaccine was immediately injected after tumor inoculation. However, FRα DNA vaccine plus CpG ODN showed a significant inhibitory effect in tumor growth. Survival curves for both animal experiments confirmed that mice immunized with pcDNA3.1/FRα plus CpG ODN had a significantly prolonged survival period than that of the pcDNA3.1 control group, the CpG ODN group or the pcDNA3.1/FRα group. The above showed that human FRα based DNA vaccination with CpG ODN as an adjuvant was effective in growth inhibition of a FRα expressing tumor in mice and deserves further evaluation as a possible immunotherapy.

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DNA vaccination against the ovarian carcinoma-associated antigen folate receptor α (FRα) induces cytotoxic T lymphocyte and antibody responses in mice

Cited by 16 publications

References 26 publications

Antitumor immunopreventive effect in mice induced by DNA vaccine encoding a fusion protein of -fetoprotein and CTLA4

Antitumor immunopreventive effect in mice induced by DNA vaccine encoding a fusion protein of -fetoprotein and CTLA4

Prevention of spontaneous neu-expressing mammary tumor development in mice transgenic for rat proto-neu by DNA vaccination

CpG oligodeoxynucleotides augment antitumor efficacy of folate receptor α based DNA vaccine

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