Interleukin-18 and the costimulatory molecule B7-1 have a synergistic anti-tumor effect on murine melanoma; Implication of combined immunotherapy for poorly immunogenic malignancy
Interleukin-18 and the costimulatory molecule B7-1 have a synergistic anti-tumor effect on murine melanoma; Implication of combined immunotherapy for poorly immunogenic malignancy
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DOI：
10.1038/sj.jid.5600685
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发表时间：
2000-05-01
影响因子：
6.5
通讯作者：
Houh, D
中科院分区：
文献类型：
--
作者：
Cho, D;Kim, TG;Houh, D
白细胞介素-18最近被描述为主要由枯否细胞分泌的细胞因子。此外，它已被证明具有显着的抗肿瘤作用，这是由T细胞和自然杀伤细胞介导的，以类似于白细胞介素-12的方式。在这里，我们报告的白细胞介素-18联合肿瘤细胞表达的B7-1（CD 80）[白细胞介素-18 + B7-1]对小鼠B16黑色素瘤在体内生长的全身给药的影响的评价。皮下接种B16黑色素瘤后，B16肿瘤在免疫活性的同系C57 BL/6小鼠中进行性生长。用白细胞介素-18处理或用B7-1转导的B16免疫的小鼠没有表现出显著的抗肿瘤作用。然而，两种治疗的组合导致黑色素瘤形成、肿瘤生长的显著抑制和生存率的显著改善。[IL-18 + B7-1]对小鼠肺转移瘤有抑制作用。此外，用[白细胞介素-18 + B7-1]处理的小鼠显示出体内自然杀伤细胞毒性和干扰素-γ产生的增加。与[白细胞介素-18 + B7-1]不同，[白细胞介素-12 + B7-1]对B16黑色素瘤没有强的抗肿瘤作用。[白细胞介素-18 + B7-1]治疗后的组织学表征证实了自然杀伤细胞浸润到肿瘤中，表明自然杀伤细胞可能参与[白细胞介素-18 + B7-1]诱导的抗肿瘤作用。通过显示在免疫前去除NK1.1（+）细胞抑制[白细胞介素-18 + B7-1]诱导的抗肿瘤作用，证实了该发现。体内CD 3（+）细胞的耗竭也降低了[白细胞介素-18 + B7-1]的抗肿瘤作用，表明CD 3（+）T细胞的重要性。总的来说，与白细胞介素-18和B7-1表达的组合对B16鼠黑素瘤具有协同抗肿瘤作用。
Interleukin-18 has been described recently as a cytokine secreted primarily by Kupffer cells. Furthermore, it has been shown that it has significant anti-tumor effects, which are mediated by T cells and natural killer cells, in a manner similar to interleukin-12. Here, we report the evaluation of the effects of the systemic administration of interleukin-18 in combination with B7-1 (CD80) expressed on tumor cells [interleukin-18 + B7-1] on the growth of murine B16 melanoma in vivo. After the subcutaneous inoculation of B16 melanoma, B16 tumors grew progressively in immunocompetent syngeneic C57BL/6 mice. Mice treated with either interleukin-18 or immunized with B7-1-transduced B16 did not demonstrate significant anti-tumor effect. The combination of the two treatments, however, resulted in dramatic suppression of melanoma formation, tumor growth, and a significant improvement in survival. Inhibitory effects of [interleukin-18 + B7-1] on lung metastasis in mice were also detected. Additionally, mice treated with [interleukin-18 + B7-1] showed an increase of natural killer cytotoxicity and interferon-gamma production in vivo. Unlike [interleukin-18 + B7-1], [interleukin-12 + B7-1] did not have a strong anti-tumor effect against B16 melanoma. Histologic characterization after the [interleukin-18 + B7-1] treatment confirmed the infiltration of natural killer cells into the tumor, suggesting that natural killer cells may be involved in the [interleukin-18 + B7-1]-induced anti-tumor effect. This finding was confirmed by showing that depletion of NK1.1(+) cells before immunization inhibits the [interleukin-18 + B7-1]-induced anti-tumor effect. Depletion of CD3(+) cells in vivo also decreased the anti-tumor effect of [interleukin-18 + B7-1], suggesting the importance of CD3(+) T cells. Collectively, combination with interleukin-18 and B7-1 expression has synergistic anti-tumor effects against B16 murine melanoma.