Immunotherapy of murine colon cancer using receptor tyrosine kinase EphA2-derived peptide-pulsed dendritic cell vaccines

Authors

  • Shinjiro Yamaguchi MD,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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    • The first two authors contributed equally to this article.

  • Tomohide Tatsumi MD, PhD,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Medical Center for Translational Research, Osaka University Hospital, Osaka, Japan
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    • The first two authors contributed equally to this article.

  • Tetsuo Takehara MD, PhD,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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  • Ryotaro Sakamori MD,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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  • Akio Uemura MD,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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  • Tsunekazu Mizushima MD, PhD,

    1. Department of Surgery, Rinku General Medical Center, Izumisano Municipal Hospital, Osaka, Japan
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  • Kazuyoshi Ohkawa MD, PhD,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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  • Walter J. Storkus PhD,

    1. Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    2. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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  • Norio Hayashi MD, PhD

    Corresponding author
    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
    • Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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    • Fax: (011) 81-6-6879-3629


Abstract

BACKGROUND.

Further optimization of dendritic cell (DC)-based vaccines is required clinically against advanced stage cancer. Given the broad range of expression levels observed in the recently defined tumor antigen EphA2 in a diverse types of cancers, especially in advanced stage or metastatic cancers, the authors evaluated the effectiveness of vaccination using DCs pulsed with EphA2-derived peptides (Eph-DCs) in a murine colon cancer model.

METHODS.

EphA2 protein expression levels were evaluated in advanced colorectal carcinoma tissues from 10 patients by Western blot analysis. C57BL/6 mice were immunized with Eph-DCs twice weekly. Interferon γ (IFN-γ) ELISPOT assays were used for the analysis of CD8-positive T cells that were specific for EphA2-derived peptide. Immunized mice were challenged subcutaneously with EphA2-positive murine colorectal adenocarcinoma (MC38) mouse colon tumors or with EphA2-negative BL6 melanoma tumors. In some experiments, mice were injected with anti-CD8, anti-CD4, or antiasialo GM1 antibody to deplete corresponding lymphocyte subsets.

RESULTS.

Among 10 samples of advanced colorectal carcinoma, 6 samples (60%) overexpressed EphA2. IFN-γ ELISPOT assays revealed that EphA2-derived peptide-specific CD8-positive T cells were generated by immunization with Eph-DCs. Immunization with Eph-DCs inhibited MC38 tumor growth compared with immunization using unpulsed DCs or phosphate-buffered saline. In contrast, Eph-DC vaccination had no effect on BL6 growth. Antibody depletion studies revealed that both CD8-positive T cells and CD4-positive T cells, but not natural killer cells, played critical roles in the efficacy observed for immunizations with Eph-DCs. Eph-DC vaccines resulted in long-term antitumor immunity against a rechallenge with MC38 tumor cells.

CONCLUSIONS.

The current results demonstrated that Eph-DC vaccines may represent a promising preventative/therapeutic modality in the cancer setting. Cancer 2007. © 2007 American Cancer Society.

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