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 (alphaGCDC) 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 alphaGCDC administration in comparison with p53 peptide-pulsed DCs using a well-established murine CMS4 tumor model. Injection of alphaGCDC 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 alphaGCDC-treated mice were significantly higher than those of pepDC-treated mice. Hepatic NK cells were efficiently activated by alphaGCDC injection and played a critical role in liver tumor rejection as evidenced by an in vivo antibody-mediated NK cell depletion study. Injection of alphaGCDC 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 alphaGCDC injection became resistant to subcutaneous CMS4 rechallenge, but not to Colon26 rechallenge.


CONCLUSIONS
These results demonstrate that alphaGCDC injection into the liver can efficiently activate NK cells that in turn reject liver tumors to establish potent acquired immunity against the original tumor.
Tatsumi
Tomohide
T
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Takehara
Tetsuo
T
Yamaguchi
Shinjiro
S
Sasakawa
Akira
A
Sakamori
Ryotaro
R
Ohkawa
Kazuyoshi
K
Kohga
Keisuke
K
Uemura
Akio
A
Hayashi
Norio
N
D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects*; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology*; D007113:Immunity, Innate; D007167:Immunotherapy / Q000379:methods; D007267:Injections; D007371:Interferon-gamma / Q000097:blood; D007694:Killer Cells, Natural / Q000473:pathology / Q000502:physiology; D008113:Liver Neoplasms / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016159:Tumor Suppressor Protein p53 / Q000494:pharmacology
D005699:Galactosylceramides; D016159:Tumor Suppressor Protein p53; C493154:alpha-galactosylceramide; D007371:Interferon-gamma