Intrahepatic delivery of alpha-galactosylceramide-pulsed dendritic cells suppresses liver tumor.
Intrahepatic delivery of alpha-galactosylceramide-pulsed dendritic cells suppresses liver tumor.
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发表时间：
2007
期刊：
影响因子：
13.5
通讯作者：
T. Tatsumi;T. Takehara;Shinjiro Yamaguchi;Akira Sasakawa;R. Sakamori;K. Ohkawa;Keisuke Kohga;A. Uemura;N. Hayashi
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作者：
T. Tatsumi;T. Takehara;Shinjiro Yamaguchi;Akira Sasakawa;R. Sakamori;K. Ohkawa;Keisuke Kohga;A. Uemura;N. Hayashi
未标记的 α-半乳糖神经酰胺是一种鞘糖脂，介导树突状细胞 (DC) 和 NKT 细胞的相互作用，从而激活先天性和获得性免疫。对于癌症治疗，已经尝试过传统的基于 DC 的疫苗，但其针对肝癌的临床疗效有限。尚未在含有丰富免疫细胞（如 NK、NKT 和 T 细胞）的肝脏中进行肝内注射 α-半乳糖神经酰胺脉冲 DC（αGCDC）的测试。在本研究中，我们使用完善的小鼠 CMS4 肿瘤模型检查了 alphaGCDC 给药与 p53 肽脉冲 DC 的疗效比较。将 alphaGCDC 注射到 CMS4 肝脏肿瘤中会导致肿瘤完全排斥并建立动物的长期生存，而注射 p53(232-240) 肽脉冲 DC (pepDC) 仅部分抑制肝脏中的肿瘤生长。 αGCDC处理的小鼠血清中IFN-γ的水平显着高于pepDC处理的小鼠。体内抗体介导的 NK 细胞耗竭研究证明，αGCDC 注射可有效激活肝 NK 细胞，并在肝肿瘤排斥中发挥关键作用。将 alphaGCDC 注射到肝肿瘤中会导致比 pepDC 更高的 p53(232-240) 肽特异性 CD8+ T 细胞反应。通过注射αGCDC而免受CMS4肝肿瘤影响的小鼠对皮下CMS4再攻击产生了抵抗力，但对Colon26再攻击没有抵抗力。结论 这些结果表明，将 alphaGCDC 注射到肝脏中可以有效激活 NK 细胞，从而排斥肝脏肿瘤，从而建立针对原始肿瘤的有效获得性免疫。
UNLABELLED 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. CONCLUSION 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.