Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity
Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity
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DOI：
10.1038/6995
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发表时间：
1999-03-01
影响因子：
46.9
通讯作者：
Kwak, LW
中科院分区：
文献类型：
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作者：
Biragyn, A;Tani, K;Kwak, LW
我们将一种模型、同基因、非免疫原性肿瘤抗原与促炎趋化因子融合，将其转化为疫苗。将两种趋化因子干扰素诱导蛋白10和单核细胞趋化蛋白3与淋巴瘤免疫球蛋白可变区(SFV)融合。SFV-趋化因子融合蛋白在体外可诱导趋化反应，在体内可诱导炎症反应。此外，在两个独立的模型中，与现有最好的蛋白质疫苗相比，编码相应融合基因的DNA构建体疫苗对大型肿瘤挑战(最小致死剂量的20倍)产生了更好的保护。免疫不是由对照组引起的，包括与无关的SFV融合；与缺乏受体结合和趋化活性的截短趋化因子融合；游离趋化因子和SFV蛋白的混合物；或编码未连接的SFV和趋化因子的裸质粒疫苗。对构象完整的SFV和功能活跃的趋化因子的联系的要求强烈表明，这些作用背后的机制是针对抗原提呈细胞(APC)的新靶向，以获得趋化因子受体介导的抗原摄取，而不是简单地通过趋化因子将APC募集到肿瘤上。最后，除了优越的效力，这些融合与淋巴瘤Ig融合与粒细胞-巨噬细胞集落刺激因子或其他细胞因子的融合因其诱导关键效应T细胞而不同。
We converted a model, syngeneic, nonimmunogenic tumor antigen into a vaccine by fusing it with a proinflammatory chemokine. Two chemokines, interferon inducible protein 10 and monocyte chemotactic protein 3, were fused to lymphoma Ig variable regions (sFv). The sFv-chemokine fusion proteins elicited chemotactic responses in vitro and induced inflammatory responses in vivo. Furthermore, in two independent models, vaccination with DNA constructs encoding the corresponding fusions generated superior protection against a large tumor challenge (20 times the minimum lethal dose), as compared with the best available protein vaccines. Immunity was not elicited by controls, including fusions with irrelevant sFv; fusions with a truncated chemokine that lacked receptor binding and chemotactic activity; mixtures of free chemokine and sFv proteins; or naked DNA plasmid vaccines encoding unlinked sFv and chemokine. The requirement for linkage of conformationally intact sFv and functionally active chemokine strongly suggested that the mechanism underlying these effects was the novel targeting of antigen presenting cells (APC) for chemokine receptor-mediated uptake of antigen, rather than the simple recruitment of APC to tumor by the chemokine. Finally, in addition to superior potency, these fusions were distinguished from lymphoma Ig fusions with granulocyte-macrophage colony-stimulating factor or other cytokines by their induction of critical effector T cells.