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Intratumoral electroporation of IL-12 cDNA eradicates established melanomas by Trp2180–188-specific CD8+ CTLs in a perforin/granzyme-mediated and IFN-γ-dependent manner: application of Trp2180–188 peptides

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Abstract

Intratumoral electroporation (IT-EP) with IL-12 cDNA (IT-EP/IL12) can lead to the eradication of established B16 melanoma tumors in mice. Here, we explore the immunological mechanism of the antitumor effects generated by this therapy. The results show that IT-EP/IL12 applied only once resulted in eradication in 70% animals with large established B16 tumors. Tumor eradication required the participation of CD8+ T cells, but not CD4+ T cells and NK cells. IT-EP/IL12 induced antigen-specific CD8+ T cell responses against the immunodominant Trp2180–188 epitope and generated a systemic response, resulting in significant therapeutic effects against distal, untreated tumors. The therapeutic effect of IT-EP/IL12 was absent in perforin-deficient mice, indicating that tumor elimination occurred through conventional perforin/granzyme lysis by CTLs. Moreover, this therapy induced some degree of immunological memory that protected approximately one-third of the cured mice against a subsequent tumor challenge. Moreover, antitumor efficacy and long-term protection against B16 were significantly improved by concurrent Trp2 peptide immunization through more induction of Ag-specific CTL responses and more attraction of IFN-γ-expressing CD8+ T cells into tumor sites. The antitumor effect of IT-EP/IL12 required the participation of IFN-γ, which was shown to induce MHC class I expression on B16 cells and increase the lytic activity of the CD8+ CTL generated by IT-EP/IL12. The results from these animal studies may help in the development of IT-EP/IL12 for cancer patients.

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Acknowledgments

We wish to appreciate VGX International Inc./Inovio for providing Cellectra® for this study. We would also like to thank Yechan Sim and Ja Young Gu for their animal care. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0008060).

Conflict of interest

Jeong-Im Sin serves as a consultant to VGX International Inc. All other authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-701, Korea

    Jeong-Im Sin & Jongseon Choe

  2. Department of Pathology, School of Medicine, Catholic University of Daegu, 3056-6 Daemyung-4-Dong, Namgu, Daegu, 705-718, Korea

    Jae-Bok Park

  3. Department of Nephrology, School of Medicine, Catholic University of Daegu, 3056-6 Daemyung-4-Dong, Namgu, Daegu, 705-718, Korea

    In Hee Lee

  4. Department of Plastic Surgery, School of Medicine, Catholic University of Daegu, 3056-6 Daemyung-4-Dong, Namgu, Daegu, 705-718, Korea

    Daehan Park

  5. Department of Obstetrics and Gynecology, School of Medicine, Catholic University of Daegu, 3056-6 Daemyung-4-Dong, Namgu, Daegu, 705-718, Korea

    Youn Seok Choi

  6. Immunology Program, Department of Oncologic Sciences, Moffitt Cancer Center, University of South Florida, Tampa, FL, 33612, USA

    Esteban Celis

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  1. Jeong-Im Sin
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Sin, JI., Park, JB., Lee, I.H. et al. Intratumoral electroporation of IL-12 cDNA eradicates established melanomas by Trp2180–188-specific CD8+ CTLs in a perforin/granzyme-mediated and IFN-γ-dependent manner: application of Trp2180–188 peptides. Cancer Immunol Immunother 61, 1671–1682 (2012). https://doi.org/10.1007/s00262-012-1214-8

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