DNA vaccines encoding altered peptide ligands for SSX2 enhance epitope-specific CD8+ T-cell immune responses.
DNA vaccines encoding altered peptide ligands for SSX2 enhance epitope-specific CD8+ T-cell immune responses.
复制标题
编码改变的 SSX2 肽配体的 DNA 疫苗可增强表位特异性 CD8 T 细胞免疫反应。
DOI：
10.1016/j.vaccine.2014.01.048
复制
发表时间：
2014
期刊：
影响因子：
5.5
通讯作者：
McNeel,DouglasG
中科院分区：
文献类型：
--
作者：
Smith,HeathA;Rekoske,BrianT;McNeel,DouglasG
质粒DNA是一种简单且易于修改的疫苗抗原递送形式。美国农业部批准了几种非人类疾病的DNA疫苗，强调了这种抗原递送方法作为治疗或预防包括癌症在内的人类疾病的一种具有成本效益的方法的潜力。然而，虽然DNA疫苗在早期临床试验中已经证明了安全性和免疫效果，但它们并没有始终引起强大的抗肿瘤反应。因此，最近的许多努力都在寻求提高DNA疫苗的免疫功效，我们已经专门评估了DNA疫苗编码的几种靶抗原作为人类前列腺癌的治疗方法。鉴于SSX2在转移性前列腺癌中的频繁表达，我们特别关注SSX2作为一种潜在的靶抗原。我们之前已经确定了两个肽，p41-49和p103-111，作为hla - a2限制性ssx2特异性表位。在本研究中，我们试图确定DNA疫苗的效力是否可以通过改变肽配体（APL）策略来增强，其中对这些表位的锚定残基进行修饰，以增强或减弱它们与HLA-A2的结合。一种编码APL的DNA疫苗被修饰以增加表位结合，从而引发了健壮的肽特异性CD8+ T细胞，产生针对每个表位特异性的Th1细胞因子。DNA疫苗中一个表位的消融不会增强对另一个表位的免疫应答。这些结果表明，由DNA疫苗编码的APL可以同时引发对多个表位特异性的抗原特异性T细胞数量的增加，并提示这可能是提高编码肿瘤抗原的DNA疫苗的免疫原性的一般方法。
Plasmid DNA serves as a simple and easily modifiable form of antigen delivery for vaccines. The USDA approval of DNA vaccines for several non-human diseases underscores the potential of this type of antigen delivery method as a cost-effective approach for the treatment or prevention of human diseases, including cancer. However, while DNA vaccines have demonstrated safety and immunological effect in early phase clinical trials, they have not consistently elicited robust anti-tumor responses. Hence many recent efforts have sought to increase the immunological efficacy of DNA vaccines, and we have specifically evaluated several target antigens encoded by DNA vaccine as treatments for human prostate cancer. In particular, we have focused on SSX2 as one potential target antigen, given its frequent expression in metastatic prostate cancer. We have previously identified two peptides, p41-49 and p103-111, as HLA-A2-restricted SSX2-specific epitopes. In the present study we sought to determine whether the efficacy of a DNA vaccine could be enhanced by an altered peptide ligand (APL) strategy wherein modifications were made to anchor residues of these epitopes to enhance or ablate their binding to HLA-A2. A DNA vaccine encoding APL modified to increase epitope binding elicited robust peptide-specific CD8+ T cells producing Th1 cytokines specific for each epitope. Ablation of one epitope in a DNA vaccine did not enhance immune responses to the other epitope. These results demonstrate that APL encoded by a DNA vaccine can be used to elicit increased numbers of antigen-specific T cells specific for multiple epitopes simultaneously, and suggest this could be a general approach to improve the immunogenicity of DNA vaccines encoding tumor antigens.