α-Galactosylceramide activates antitumor immunity against liver tumor

Authors

  • Tomohide Tatsumi,

    Corresponding author
    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka
      Dr Tomohide Tatsumi, Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Email: tatsumit@gh.med.osaka-u.ac.jp
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  • Tetsuo Takehara,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka
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  • Takuya Miyagi,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka
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  • Tsukasa Sugiyama,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka
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  • Hiroshi Aketa,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka
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  • Akira Sasakawa,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka
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  • Tatsuya Kanto,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka
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  • Naoki Hiramatsu,

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka
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  • Norio Hayashi

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka
    2. Kansai-Rosai Hospital, Amagasaki, Hyogo, Japan
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Dr Tomohide Tatsumi, Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Email: tatsumit@gh.med.osaka-u.ac.jp

Abstract

Aim:  α-Galactosylceramide (α-GalCer) has been attracting attention as a novel approach to treat metastatic liver cancer. We investigated the detailed process of activating liver dendritic cells (DC) and immune cells after α-GalCer treatment in the mouse liver tumor model.

Methods:  BALB/c mice bearing CMS4 liver tumor (p53 peptide-expressing tumor) were treated by α-GalCer. We evaluated the activation of liver DC and immune cells after α-GalCer treatment. Interferon (IFN)-γ enzyme-linked immunosorbent spot (ELISPOT) assay was performed to detect p53 peptide-specific cytotoxic T lymphocytes (CTL). To assess the impact of systemic acquired immunity by α-GalCer treatment, 28 days after liver tumor treatment, CMS4 cells or Colon26 cells were re-challenged s.c.

Results:  The liver weights of α-GalCer-treated mice were significantly lighter than those of vehicle-treated mice. Depletion experiments revealed that natural killer (NK) cells were essential for the antitumor effect of α-GalCer. α-GalCer treatment significantly increased the population of DC and NK cells in the liver. The expressions of co-stimulatory molecules on liver DC significantly increased with the peak at 1 day after α-GalCer administration. IFN-γ ELISPOT assay demonstrated that p53 peptide-specific CTL was generated efficiently in α-GalCer-treated mice. 51Cr-release assay revealed that CD8+, not CD4+, CTL against CMS4 cells were generated in α-GalCer-treated mice. The mice that had been protected from CMS4 liver tumor by α-GalCer injection became resistant against s.c. CMS4 re-challenge, but not against Colon26 re-challenge.

Conclusion:  These results demonstrated the therapeutic potential of α-GalCer against liver cancer through activating liver DC and immune cells in the liver.

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