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Coexpression of Flt3 ligand and GM-CSF genes modulates immune responses induced by HER2/neu DNA vaccine

Cancer Gene Therapy volume 14, pages 904–917 (2007)Cite this article

Abstract

DNA vaccine and dendritic cells (DCs)-based vaccine have emerged as promising strategies for cancer immunotherapy. Fms-like tyrosine kinase 3-ligand (Flt3L) and granulocyte–macrophage-colony-stimulating factor (GM-CSF) have been exploited for the expansion of DC. It was reported previously that combination of plasmid encoding GM-CSF with HER2/neu DNA vaccine induced predominantly CD4+ T-cell-mediated antitumor immune response. In this study, we investigated the modulation of immune responses by murine Flt3L and GM-CSF, which acted as genetic adjuvants in the forms of bicistronic (pFLAG) and monocistronic (pFL and pGM) plasmids for HER2/neu DNA vaccine (pN-neu). Coexpression of Flt3L and GM-CSF significantly enhanced maturation and antigen-presentation abilities of splenic DC. Increased numbers of infiltrating DC at the immunization site, higher interferon-γ production, and enhanced cytolytic activities by splenocytes were prominent in mice vaccinated with pN-neu in conjunction with pFLAG. Importantly, a potent CD8+ T-cell-mediated antitumor immunity against bladder tumors naturally overexpressing HER2/neu was induced in the vaccinated mice. Collectively, our results indicate that murine Flt3L and GM-CSF genes coexpressed by a bicistronic plasmid modulate the class of immune responses and may be superior to those codelivered by two separate monocistronic plasmids as the genetic adjuvants for HER2/neu DNA vaccine.

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Acknowledgements

We are indebted to TC Wu (Department of Pathology, Johns Hopkins University), LH Hwang (Hepatitis Research Center, National Taiwan University Hospital, Taiwan), and MD Lai (Department of Biochemistry and Molecular Biology, National Cheng Kung University, Taiwan) for providing pFL, pGEM-4/GM-CSF and pRc/CMV-N′-neu plasmids, respectively. This work was supported by Grants NSC 89-2318-B-006-014-M51 and 90-2318-B-006-006-M51 to A-L Shiau and NSC 89-2318-B-006-013-M51 and 90-2318-B-006-003-M51 to C-L Wu from National Science Council, Taiwan.

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Authors and Affiliations

  1. Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan

    Y-T Yo, C-C Chang, C-L Wu & A-L Shiau

  2. Department of Obstetrics and Gynecology, National Cheng Kung University Medical College, Tainan, Taiwan

    K-F Hsu

  3. Department of Urology, Department of Health, Tainan Hospital, Executive Yuan, Taiwan

    G-S Shieh

  4. Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan

    C-W Lo & A-L Shiau

  5. Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan

    C-L Wu

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Correspondence to C-L Wu or A-L Shiau.

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Yo, YT., Hsu, KF., Shieh, GS. et al. Coexpression of Flt3 ligand and GM-CSF genes modulates immune responses induced by HER2/neu DNA vaccine. Cancer Gene Ther 14, 904–917 (2007). https://doi.org/10.1038/sj.cgt.7701081

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