Intrahepatic delivery of alpha-galactosylceramide-pulsed dendritic cells suppresses liver tumor

Alpha-galactosylceramide, a glycosphingolipid, mediates interaction of dendritic cells (DCs) and NKT cells, leading to activation of both innate and acquired immunity. For cancer treatment, conventional DC-based vaccine has been tried, but its clinical efficacy is limited against liver cancer. Intrahepatic injection of alpha-Galactosylceramide-pulsed DCs (alpha GCDC) has not yet been tested in the liver that contains abundant immune cells such as NK, NKT, and T cells. In the present study, we examined the efficacy of alpha GCDC administration in comparison with p53 peptide-pulsed DCs using a well-established murine CMS4 tumor model. Injection of alpha GCDC into CMS4 liver tumors resulted in complete tumor rejection and established long-term survival of the animals, while injection of p53(232-240) peptide-pulsed DCs (pepDC) only partially suppressed tumor growth in the liver. The levels of IFN-gamma in sera of alpha GCDC-treated mice were significantly higher than those of pepDC-treated mice. Hepatic NK cells were efficiently activated by alpha GCDC injection and played a critical role in liver tumor rejection as evidenced by an in vivo antibody-mediated NK cell depletion study. Injection of alpha GCDC into liver tumor led to higher p53(232-240) peptide-specific CD8+ T cell response than that of pepDC. The mice that had been protected from CMS4 liver tumor by alpha GCDC injection became resistant to subcutaneous CMS4 rechallenge, but not to Colon26 rechallenge. Conclusion: These results demonstrate that alpha GCDC injection into the liver can efficiently activate NK cells that in turn reject liver tumors to establish potent acquired immunity against the original tumor.