An analysis for mechanism of antitumor effects of dendritic cells treated with αGalactosylceramide

α半乳糖神经酰胺处理树突状细胞的抗肿瘤作用机制分析

• 批准号: 13672079
• 负责人: HASHIMOTO Wataru
• 金额: $ 2.3万
• 依托单位: TOHOKU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672079/
• 关键词: galactosylceramide; antitumor effects; NKT cells; IFN-γ; IL-12; dendritic cells; Intratumoral injection; tumor immunotherapy

We have already reported that intratumoral injection of dendritic cells (DCs) treated with αGalactosylceramide (αGalCer) selectively activated natural killer T cells (NKT cells), resulting in regression of day 7 established poorly immunogenic tumors.To clarify a role of IL-12 produced by DCs, α-GalCer treated-DCs harvested from IL-12 deficient mice can inhibits MCA205 tumor growth as strong as using WT's DCs. Interestingly, α-GalCer injection can not enhance the in vitro cytotoxicity of lymphocytes harvested from IFN-γ-deficient mice. Furthermore, the antitumor activity of using DCs treated with α-GalCer in IFN-γ-deficient mice is impaired comopletely. These results indicate that IFN-γ, but IL-12, plays critical role in these antitumor response of α-GalCer treated-DCs.Next, we investigated the antitumor effects of αGalCer on human peripheral blood mononuclear cells (PBMC). Phenotypic analysis revealed an expansion of CD3+ CD161+ CD56- Vα24TCR+ T cells on PBMC. These results are consistent with the previous reports showing that α-GalCer selectively activates Vα14NKT cells in mice, suggesting that intratumoral injection of α-GalCer treated-DC should be considered a viable strategy for the generation of antitumor responses on human and for further clinical applications for head and neck tumors.

我们已经报道，用α半乳糖神经酰胺(αGalCer)处理的树突状细胞(DC)瘤内注射选择性地激活自然杀伤T细胞(NKT细胞)，导致第7天建立的免疫原性较差的肿瘤消退。为了阐明DC产生IL-12的作用，从IL-12缺陷小鼠获取的α-GalCer处理的DC可以像使用WT的DC一样抑制肿瘤生长。有趣的是，α-GalCer注射并不能增强干扰素-γ缺陷小鼠淋巴细胞的体外细胞毒作用。此外，用α-GalCer处理的DC对干扰素-γ缺陷小鼠的抗肿瘤活性也受到了明显的损害。这些结果表明，干扰素-γ而不是IL-12在α-GalCer处理的DC的这些抗肿瘤反应中起关键作用。接下来，我们研究了αGalCer对人外周血单个核细胞的抗肿瘤作用。表型分析显示CD3+CD16 1+CD5 6-Vα2 4TCR+T细胞在单个核细胞上呈扩增状态。这些结果与先前报道的α-GalCer选择性激活小鼠V-α14NKT细胞的结果一致，提示瘤内注射α-GalCer处理的DC可以被认为是在人类身上产生抗肿瘤反应以及进一步临床应用于头颈部肿瘤的可行策略。

项目成果

W.Hashimoto, E.Tanaka, R.D.Robbins, M.Taniguchi, H.Okamura, M.T.Lotze, H.Tahara: "NK but not NKT cells play a necessary role to promote an innate antitumor response induced by IL-18"Int. J. Cancer. 103. 508-513 (2003)

W.Hashimoto、E.Tanaka、R.D.Robbins、M.Taniguchi、H.Okamura、M.T.Lotze、H.Tahara：“NK（而非 NKT 细胞）在促进 IL-18 诱导的先天抗肿瘤反应中发挥着必要的作用”Int。

F.Tanaka, W.Hashimoto 他3名: "Therapeutic and specimunity induced by co-administration of immature dendritic cells and adenoviral vector expressing biologically active IL-18"Gene Therapy. 21. 1480-1486 (2002)

F.Tanaka、W.Hashimoto 和其他 3 人：“未成熟树突细胞和表达生物活性 IL-18 的腺病毒载体共同施用诱导的治疗和特异性免疫”基因治疗 21. 1480-1486 (2002)。

R.Tanaka, W.Hashimoto, P.D.Robbins, M.T,Lotze, H.Tahara: "Therapeutic and specific antitumor immunity induced by co-administration of immature dendritic cells and adenoviral vector expressing biologically active IL-18"Gene Therapy. 21. 1480-1486 (2002)

R.Tanaka、W.Hashimoto、P.D.Robbins、M.T、Lotze、H.Tahara：“联合施用未成熟树突状细胞和表达生物活性 IL-18 的腺病毒载体诱导治疗性和特异性抗肿瘤免疫”基因疗法。

橋元 亘 他3名: "Interleukin-18によるNatural Killer(NK)細胞活性化および腫瘍細胞のアポトーシス誘導"頭頸部腫瘍. 29. 1-7 (2003)

Wataru Hashimoto 等 3 人：“白细胞介素 18 诱导自然杀伤 (NK) 细胞活化和肿瘤细胞凋亡”，头颈肿瘤，29. 1-7 (2003)。

W.Hashimoto 他6名: "NK but not NKT cells play a necessary role to promote an innate antitumor response induced by IL-18"Int. J. Cancer. 103. 508-513 (2003)

W. Hashimoto 和其他 6 人：“NK（而非 NKT 细胞）在促进 IL-18 诱导的先天抗肿瘤反应中发挥着必要的作用”，《癌症杂志》103. 508-513 (2003)。