OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice.
OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice.
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DOI：
10.1172/jci32693
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发表时间：
2007-11
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影响因子：
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通讯作者：
J. Zaini;S. Andarini;M. Tahara;Y. Saijo;N. Ishii;K. Kawakami;M. Taniguchi;K. Sugamura;T. Nukiwa;T. Kikuchi
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文献类型：
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作者：
J. Zaini;S. Andarini;M. Tahara;Y. Saijo;N. Ishii;K. Kawakami;M. Taniguchi;K. Sugamura;T. Nukiwa;T. Kikuchi
DC 卓越的免疫刺激能力使其成为癌症免疫治疗研究的潜在靶标。我们在小鼠中发现，TNF-α刺激的 DC 成熟伴随着 OX40 配体 (OX40L) 表达的增加，缺乏这种配体会导致成熟 DC 无法产生细胞抗肿瘤免疫。此外，瘤内施用经过修饰以表达 OX40L 的 DC，通过产生由 CD4+ T 细胞和 NKT 细胞介导的肿瘤特异性溶细胞 T 细胞反应来抑制肿瘤生长。在用表达 OX40L 的 DC 治疗的肿瘤中，NKT 细胞群显着增加，并表现出高水平的 IFN-γ 产生，这对于抗肿瘤免疫至关重要。其他评估 NKT 细胞活化状态（IFN-γ 产生和 CD69 表达）的研究表明，NKT 细胞上 OX40 表达增强了在 CD1d 背景下呈递 α-半乳糖神经酰胺的 DC 的 NKT 细胞活化作用。这些结果表明，DC 上的 OX40L 通过与 NKT 细胞和 CD4+ T 细胞上的 OX40 结合，在荷瘤小鼠的抗肿瘤免疫诱导中发挥着关键作用。
The exceptional immunostimulatory capacity of DCs makes them potential targets for investigation of cancer immunotherapeutics. We show here in mice that TNF-alpha-stimulated DC maturation was accompanied by increased expression of OX40 ligand (OX40L), the lack of which resulted in an inability of mature DCs to generate cellular antitumor immunity. Furthermore, intratumoral administration of DCs modified to express OX40L suppressed tumor growth through the generation of tumor-specific cytolytic T cell responses, which were mediated by CD4+ T cells and NKT cells. In the tumors treated with OX40L-expressing DCs, the NKT cell population significantly increased and exhibited a substantial level of IFN-gamma production essential for antitumor immunity. Additional studies evaluating NKT cell activation status, in terms of IFN-gamma production and CD69 expression, indicated that NKT cell activation by DCs presenting alpha-galactosylceramide in the context of CD1d was potentiated by OX40 expression on NKT cells. These results show a critical role for OX40L on DCs, via binding to OX40 on NKT cells and CD4+ T cells, in the induction of antitumor immunity in tumor-bearing mice.