PURPOSE: Dendritic cell (DC) vaccines are a promising immunotherapeutic approach for treatment and prevention of cancer. While this methodology is widely accepted, it also has some limitations. Antigen-presenting cells including DCs express the mannan receptor (MR). The delivery of a mannan-modified tumor antigen to the MR has been demonstrated to be efficient. Vascular endothelial growth factor receptor-2 (VEGFR-2) is mainly responsible for angiogenesis and tumor growth. The goal of our study was to deliver VEGFR-2 to DCs by means of mannan-modified adenovirus. METHODS: VEGFR-2 recombinant adenovirus modified with oxidized mannan was constructed as a tumor vaccine to immunize mice in vivo. IFN-γ in mouse sera and spleen was detected by ELISA and ELISPOT. The killing activity of cytotoxic T lymphocyte (CTL) against VEGFR-2 was measured with a lactate dehydrogenase assay. Vessel densities in tumor tissues were detected by immunohistochemistry. Flow cytometry was used to test CD4(+) and CD8(+) T-cell counts in tumor tissues. RESULTS: The vaccine exhibited both protective and therapeutic efficacy in the inhibition of tumor growth and markedly prolonged survival in mice. Protection against metastasis was also observed. Furthermore, vaccination led to greater IFN-γ and VEGFR-2-specific CTLs. The specific immunity resulted in the suppression of angiogenesis and an increase in CD8(+) cells in tumor tissues. CONCLUSION: Oxidized mannan-modified adenovirus expressing VEGFR-2 could extraordinarily stimulate both protective and therapeutic immune response in a mice model. Our data suggest that the combination of cancer immunity and anti-angiogenesis via modified mannan is a promising strategy in tumor prophylaxis and therapy.
PURPOSE: Dendritic cell (DC) vaccines are a promising immunotherapeutic approach for treatment and prevention of cancer. While this methodology is widely accepted, it also has some limitations. Antigen-presenting cells including DCs express the mannan receptor (MR). The delivery of a mannan-modified tumor antigen to the MR has been demonstrated to be efficient. Vascular endothelial growth factor receptor-2 (VEGFR-2) is mainly responsible for angiogenesis and tumor growth. The goal of our study was to deliver VEGFR-2 to DCs by means of mannan-modified adenovirus. METHODS:VEGFR-2 recombinant adenovirus modified with oxidized mannan was constructed as a tumor vaccine to immunize mice in vivo. IFN-γ in mouse sera and spleen was detected by ELISA and ELISPOT. The killing activity of cytotoxic T lymphocyte (CTL) against VEGFR-2 was measured with a lactate dehydrogenase assay. Vessel densities in tumor tissues were detected by immunohistochemistry. Flow cytometry was used to test CD4(+) and CD8(+) T-cell counts in tumor tissues. RESULTS: The vaccine exhibited both protective and therapeutic efficacy in the inhibition of tumor growth and markedly prolonged survival in mice. Protection against metastasis was also observed. Furthermore, vaccination led to greater IFN-γ and VEGFR-2-specific CTLs. The specific immunity resulted in the suppression of angiogenesis and an increase in CD8(+) cells in tumor tissues. CONCLUSION: Oxidized mannan-modified adenovirus expressing VEGFR-2 could extraordinarily stimulate both protective and therapeutic immune response in a mice model. Our data suggest that the combination of cancer immunity and anti-angiogenesis via modified mannan is a promising strategy in tumor prophylaxis and therapy.
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Authors: Dafni Chondronasiou; Tracy-Jane T H D Eisden; Anita G M Stam; Qiana L Matthews; Mert Icyuz; Erik Hooijberg; Igor Dmitriev; David T Curiel; Tanja D de Gruijl; Rieneke van de Ven Journal: Vaccines (Basel) Date: 2018-07-18