Potent antitumor activity of interleukin-27
Potent antitumor activity of interleukin-27
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DOI：
10.1158/0008-5472.can-03-2084
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发表时间：
2004-02-01
期刊：
影响因子：
11.2
通讯作者：
Yoshimoto, T
中科院分区：
文献类型：
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作者：
Hisada, M;Kamiya, S;Yoshimoto, T
尽管在动物模型中有许多有希望的数据表明白细胞介素（IL）-12可能是一种强大的抗肿瘤治疗剂，但其过度的毒性已成为其临床应用的问题。IL-27是一种新的IL-12家族成员，在T辅助细胞1启动的早期调节中发挥作用，包括诱导T-bet和IL-12受体β 2表达。在本研究中，我们评估了IL-27对小鼠结肠癌C26肿瘤模型的抗肿瘤活性。用单链IL-27 cDNA转导并分泌IL-27（C26-IL-27）的C26细胞在体内表现出最小的肿瘤生长，并且接种这些细胞的所有小鼠都健康地存活，肿瘤完全缓解。用C26-IL-27接种小鼠诱导脾细胞中IFN-γ产生和针对C26肿瘤的细胞毒性T淋巴细胞活性增强。接种的存活小鼠对随后的亲代C26肿瘤攻击表现出肿瘤特异性保护性免疫。IL-27的抗肿瘤活性在裸鼠中几乎被降低，并且在免疫活性小鼠中CD 8（+）T细胞的耗竭和IFN-γ的中和大大降低了抗肿瘤活性。此外，在T-bet缺陷小鼠中消除了抗肿瘤活性，而在信号转导子和转录激活子（STAT）4缺陷小鼠中意外地观察到抗肿瘤活性。这些结果表明，IL-27具有诱导肿瘤特异性抗肿瘤活性和保护性免疫的有效能力，并且抗肿瘤活性主要通过CD 8（+）T细胞、IFN-γ和T-bet介导，但不通过STAT 4介导。
Although much promising data that interleukin (IL)-12 could be a powerful therapeutic agent against cancer were reported in animal models, its excessive toxicity has become a problem for its clinical application. IL-27 is a novel IL-12 family member that plays a role in the early regulation of T helper cell 1 initiation, including induction of T-bet and IL-12 receptor beta2 expression. In the present study, we have evaluated the antitumor activity of IL-27 against a murine tumor model of colon carcinoma C26. C26 cells, which were transduced with the single-chain IL-27 cDNA and became secreting IL-27 (C26-IL-27), exhibited minimal tumor growth in vivo, and all of the mice inoculated with these cells survived healthily with complete tumor remission. Inoculation of mice with C26-IL-27 induced enhanced IFN-gamma production and cytotoxic T-lymphocyte activity against C26 tumor in spleen cells. Recovered mice from the inoculation showed a tumor-specific protective immunity to the following challenge with parental C26 tumor. The antitumor activity of IL-27 was almost diminished in nude mice, and depletion of CD8(+) T cells and neutralization of IFN-gamma in immunocompetent mice reduced greatly the antitumor activity. Moreover, the antitumor activity was abolished in T-bet-deficient mice, whereas it was observed unexpectedly in mice deficient of signal transducer and activator of transcription (STAT) 4. These results suggest that IL-27 has potent abilities to induce tumor-specific antitumor activity and protective immunity and that the antitumor activity is mediated mainly through CD8(+) T cells, IFN-gamma, and T-bet but not through STAT4.