Department of Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA.
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Vaccine. 2014 Mar 26;32(15):1707-15. doi: 10.1016/j.vaccine.2014.01.048. Epub 2014 Jan 31.
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.
质粒 DNA 可作为一种简单且易于修饰的抗原传递形式，用于疫苗。美国农业部对几种非人类疾病的 DNA 疫苗的批准，突显了这种抗原传递方法作为一种具有成本效益的方法，用于治疗或预防人类疾病（包括癌症）的潜力。然而，尽管 DNA 疫苗在早期临床试验中已显示出安全性和免疫效果，但它们并未始终引起强烈的抗肿瘤反应。因此，最近许多努力都旨在提高 DNA 疫苗的免疫效力，我们特别评估了几种由 DNA 疫苗编码的靶抗原，作为治疗人类前列腺癌的方法。特别是，我们专注于 SSX2 作为一种潜在的靶抗原，因为它在转移性前列腺癌中频繁表达。我们之前已经确定了两个肽段，p41-49 和 p103-111，作为 HLA-A2 限制性 SSX2 特异性表位。在本研究中，我们试图确定改变肽配体（APL）策略是否可以增强 DNA 疫苗的功效，该策略对这些表位的锚定残基进行修饰，以增强或消除它们与 HLA-A2 的结合。一种编码经修饰以增加表位结合的 APL 的 DNA 疫苗，可引发强烈的肽特异性 CD8+T 细胞，产生针对每个表位的 Th1 细胞因子。在 DNA 疫苗中消除一个表位不会增强对另一个表位的免疫反应。这些结果表明，DNA 疫苗编码的 APL 可用于同时引发针对多个表位的大量抗原特异性 T 细胞，并且表明这可能是提高编码肿瘤抗原的 DNA 疫苗免疫原性的一般方法。
