Tumor cells loaded with α-galactosylceramide induce innate NKT and NK cell-dependent resistance to tumor implantation in mice
Tumor cells loaded with α-galactosylceramide induce innate NKT and NK cell-dependent resistance to tumor implantation in mice
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DOI：
10.4049/jimmunol.178.5.2853
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Fujii, Shin-ichiro
中科院分区：
文献类型：
--
作者：
Shimizu, Kanako;Goto, Akira;Fujii, Shin-ichiro
已知负载α-半乳糖神经酰胺（α-GalCer）的树突状细胞（DC）是用于刺激体内先天性NKT和NK细胞应答的活性APC。在这项研究中，我们评估了非DC在体外和体内呈递α-GalCer的能力，特别是负载α-GalCer的肿瘤细胞（肿瘤/Gal）。即使肿瘤细胞缺乏⑶ 40、⑶ 80和⑶ 86共刺激分子的表达，静脉内注射肿瘤/Gal也导致NKT和NK细胞分泌IFN-γ。这些对肿瘤/Gal的先天应答，包括IL-12 p70的诱导，与负载α-GalCer的DC相当或更好。稳定转导以表达更高水平的CD 1d的B16黑素瘤细胞显示相对于野生型1316细胞在体内呈递α-GalCer的能力增加。三种不同的肿瘤细胞系，当加载有α-GalCer时，在静脉内注射后未能建立肿瘤，并且小鼠存活至少6个月。对肿瘤细胞的抵抗不依赖于CD 4和CD 8 T细胞，而依赖于NKT和NK细胞。如果在给予活B16肿瘤细胞后3小时或3天注射CD 1d高-α-GalCer负载的B16肿瘤细胞（有或无辐射），则小鼠可免受转移的发展。总之，这些结果表明肿瘤/Gal是先天性NKT和NK细胞应答的有效APC，并且这些先天性免疫应答能够抵抗体内转移的建立。
Dendritic cells (DCs) loaded with alpha-galactosylceramide (alpha-GalCer) are known to be active APCs for the stimulation of innate NKT and NK cell responses in vivo. In this study, we evaluated the capacity of non-DCs to present alpha-GalCer in vitro and in vivo, particularly tumor cells loaded with alpha-GalCer (tumor/Gal). Even though the tumor cells lacked expression of CD40, CD80, and CD86 costimulatory molecules, the i.v. injection of tumor/Gal resulted in IFN-gamma secretion by NKT and NK cells. These innate responses to tumor/Gal, including the induction of IL-12p70, were comparable to or better than alpha-GalCer-loaded DCs. B16 melanoma cells that were stably transduced to express higher levels of CD1d showed an increased capacity relative to wild-type 1316 cells to present alpha-GalCer in vivo. Three different tumor cell lines, when loaded with alpha-GalCer, failed to establish tumors upon i.v. injection, and the mice survived for at least 6 mo. The resistance against tumor cells was independent of CD4 and CD8 T cells but dependent upon NKT and NK cells. Mice were protected from the development of metastases if the administration of live B16 tumor cells was followed 3 h or 3 days later by the injection of CD1d high-alpha-GalCer-loaded B16 tumor cells with or without irradiation. Taken together, these results indicate that tumor/Gal are effective APCs for innate NKT and NK cell responses, and that these innate immune responses are able to resist the establishment of metastases in vivo.