α-Galactosylceramide activates antitumor immunity against liver tumor

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.

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.

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. (51) Cr-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.

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