Intrahepatic delivery of α-galactosylceramide-pulsed... : Hepatology (original) (raw)
Original Articles
Intrahepatic delivery of α-galactosylceramide-pulsed dendritic cells suppresses liver tumor
Tatsumi, Tomohide1; Takehara, Tetsuo1; Yamaguchi, Shinjiro1; Sasakawa, Akira1; Sakamori, Ryotaro1; Ohkawa, Kazuyoshi1; Kohga, Keisuke1; Uemura, Akio1; Hayashi, Norio1*
1 Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
*Address reprint requests to: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Email:[email protected];
Received 13 July 2006; Accepted 5 October 2006
Published online in Wiley InterScience (www.interscience.wiley.com).
Grant sponsor: Ministry of Education, Culture, Sports, Science, and Technology of Japan; Grant sponsor: Ministry of Health, Labor, and Welfare of Japan.
Potential conflict of interest: Nothing to report.
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Abstract
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 α-Galactosylceramide-pulsed DCs (αGCDC) 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 αGCDC administration in comparison with p53 peptide-pulsed DCs using a well-established murine CMS4 tumor model. Injection of αGCDC into CMS4 liver tumors resulted in complete tumor rejection and established long-term survival of the animals, while injection of p53232-240 peptide-pulsed DCs (pepDC) only partially suppressed tumor growth in the liver. The levels of IFN-γ in sera of αGCDC-treated mice were significantly higher than those of pepDC-treated mice. Hepatic NK cells were efficiently activated by αGCDC injection and played a critical role in liver tumor rejection as evidenced by an in vivo antibody-mediated NK cell depletion study. Injection of αGCDC into liver tumor led to higher p53232-240 peptide-specific CD8+ T cell response than that of pepDC. The mice that had been protected from CMS4 liver tumor by αGCDC injection became resistant to subcutaneous CMS4 rechallenge, but not to Colon26 rechallenge. Conclusion : These results demonstrate that αGCDC injection into the liver can efficiently activate NK cells that in turn reject liver tumors to establish potent acquired immunity against the original tumor. (Hepatology 2007;45:22–30.)
Abbreviations: APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte; DC, dendritic cell; α-GalCer, α-galactosylceramide; MNC, mononuclear cell; PBS, phosphate-buffered saline.
Copyright © 2007 American Association for the Study of Liver Diseases.