Enantiospecific adjuvant activity of cationic lipid DOTAP in cancer vaccine
Enantiospecific adjuvant activity of cationic lipid DOTAP in cancer vaccine
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DOI：
10.1007/s00262-011-0970-1
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发表时间：
2011-05-01
影响因子：
5.8
通讯作者：
Huang, Leaf
中科院分区：
文献类型：
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作者：
Vasievich, Elizabeth A.;Chen, Weihsu;Huang, Leaf
可商购获得的DOTAP是两种对映异构体的外消旋混合物。在建立的鼠宫颈癌模型中，使用肽/脂质复合物作为治疗性疫苗检查每种异构体的佐剂性。这种简单的疫苗由阳离子脂质（DOTAP）和人乳头瘤病毒（HPV）16蛋白E7的主要组织相容性复合体（MHC）I类限制性表位组成。已经完成了外消旋DOTAP/E7、（R）-DOTAP/E7和（S）-DOTAP/E7的剂量依赖性肿瘤消退实验。用（R）-DOTAP/E7复合物治疗的荷瘤小鼠显示出与用具有E7肽的外消旋DOTAP治疗的那些小鼠相当的剂量依赖性方式的肿瘤消退。这些数据得到了（R）-DOTAP/E7接种小鼠中CD 8（+）脾细胞产生IFN-γ、体内细胞毒性T淋巴细胞（CTL）应答、CD 8（+）肿瘤浸润淋巴细胞（TIL）和CD 8（+）TIL产生IFN-γ的支持。当递送（S）-DOTAP/E7时，肿瘤进展被延迟。虽然在用（S）-DOTAP/E7接种的小鼠中，CD 8（+）脾细胞不产生IFN-γ，但存在CD 8（+）TIL产生IFN-γ，这支持了我们的假设，即（S）-DOTAP具有有限的活性。还评价了对映体制剂对骨髓来源的树突状细胞的活化，以及细胞因子的产生和毒性，各组之间没有显著差异。结果表明，DOTAP对映体在体内作为佐剂的作用不同，其中（R）-DOTAP在刺激CD 8（+）抗肿瘤反应方面更有效。
Commercially available DOTAP is a racemic mixture of two enantiomers. The adjuvanticity of each isomer was examined using a peptide/lipid complex as a therapeutic vaccine in an established murine cervical cancer model. This simple vaccine consists of a cationic lipid (DOTAP) and a major histocompatibility complex (MHC) class I-restricted epitope of the Human Papillomavirus (HPV) 16 protein E7. Dose-dependent tumor regression experiments have been completed for racemic DOTAP/E7, (R)-DOTAP/E7 and (S)-DOTAP/E7. Tumor-bearing mice treated with (R)-DOTAP/E7 complexes have shown tumor regression in a dose-dependent manner comparable to those mice treated with a racemic DOTAP with E7 peptide. These data are supported by IFN-gamma production by CD8(+) splenocytes, in vivo cytotoxic T-lymphocytes (CTL) response, CD8(+) tumor-infiltrating lymphocytes (TIL), and IFN-gamma production by CD8(+) TIL in (R)-DOTAP/E7-vaccinated mice. When (S)-DOTAP/E7 is delivered, tumor progression is delayed. While IFN-gamma production is absent from CD8(+) splenocytes in mice vaccinated with (S)-DOTAP/E7, IFN-gamma production by CD8(+) TIL is present, supporting our hypothesis that (S)-DOTAP has limited activity. Activation of bone marrow-derived dendritic cells by the enantiomeric formulations has also been evaluated, as well as cytokine production and toxicity with no considerable differences between the groups. The results show the DOTAP enantiomers act differently as adjuvants in vivo, with (R)-DOTAP being more effective at stimulating a CD8(+) anti-tumor response.