High antitumor activity of RLI, an interleukin-15 (IL-15)-IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer
High antitumor activity of RLI, an interleukin-15 (IL-15)-IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer
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DOI：
10.1158/1535-7163.mct-09-0275
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发表时间：
2009-09-01
影响因子：
5.7
通讯作者：
Jacques, Yannick
中科院分区：
文献类型：
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作者：
Bessard, Anne;Sole, Veronique;Jacques, Yannick
白细胞介素（IL）-15在肿瘤免疫监视中具有重要作用，并且在肿瘤免疫治疗中具有预期用途。我们先前已经设计了融合蛋白RLI，其由IL-15受体α的NH（2）-末端（氨基酸1-77，sushi+）结构域通过接头偶联至IL-15组成，并且显示其在体外显示出比IL-15好得多的功效。在本报告中，我们使用两种不同的动物模型在体内研究了RLI是否是比IL-15和IL-2更好的癌症治疗替代品。将B16 F10小鼠黑素瘤细胞分别静脉内或脾内注射到C57 BL/6小鼠中以用于肺或肝转移。将HCT-116人结直肠癌细胞注射到裸鼠盲肠中。我们表明，RLI具有比IL-15或IL-2更高的效率，以减少肺和肝转移，并提高小鼠B16 F10黑色素瘤模型中的存活率，这一结果与体内更高的半衰期相关。我们还发现，使用抗脱唾液酸GM 1抗体在体内耗尽自然杀伤细胞，RLI的抗肿瘤作用被完全消除。此外，RLI也有效地减少50%的肿瘤生长和人结肠癌细胞在原位裸鼠模型中的转移进展。融合蛋白RLI在两种不同的癌症模型中显示出强烈的抗癌作用，通过增加其生物利用度和效率克服了IL-15的有限作用。这些发现对于使用RLI作为潜在的佐剂/治疗剂具有重要意义。[Mol Cancer Ther 2009;8（9）：2736-45]
Interleukin (IL)-15 has an important role in tumor immuno-surveillance and has a contemplated use in tumor immunotherapy. We have previously engineered the fusion protein RLI, composed of the NH(2)-terminal (amino acids 1-77, sushi+) domain of IL-15 receptor alpha coupled via a linker to IL-15, and shown that it displayed far better efficacy than IL-15 in vitro. In this report, we investigated in vivo whether RLI would be a better alternative than IL-15 and IL-2 for cancer treatment using two distinct animal models. B16F10 mouse melanoma cells were injected in C57BL/6 mice either i.v. or intrasplenically for lung or liver metastasis, respectively. HCT-116 human colorectal cancer cells were injected in the cecum of nude mice. We show that RLI has a higher efficiency than IL-15 or IL-2 to reduce lung and liver metastasis and enhance survival in the mouse B16F10 melanoma model, a result that was associated with a higher half-life in vivo. We also found that the antitumoral effect of RLI was completely abolished by in vivo depletion of natural killer cells using anti-asialoGM1 antibody. Moreover, RLI was also efficient to reduce by 50% tumor growth and the progression of metastasis of human colon carcinoma cells in an orthotopic nude mouse model. The fusion protein RLI has revealed strong anticancer effect in two different cancer models overcoming the limited effect of IL-15 by increasing its bioavailability and efficiency. These findings hold significant importance for the use of RLI as a potential adjuvant/therapeutic. [Mol Cancer Ther 2009;8(9):2736-45]