School of Medical Sciences, RMIT University, Plenty Road, Bundoora 3083, Victoria, Australia.
Bio-Organic and Medicinal Chemistry Laboratory, Burnet Institute, 85 Commercial Rd, Melbourne 3004, Australia.
Molecules. 2018 Sep 2;23(9):2233. doi: 10.3390/molecules23092233.
Peptide-based vaccines for cancer have many advantages however, for optimization these immunogens should incorporate peptide epitopes that induce CD8, as well as CD4 responses, antibody and long term immunity. Cell penetrating peptides (CPP) with a capacity of cytosolic delivery have been used to deliver antigenic peptides and proteins to antigen presenting cells to induce cytotoxic T cell, helper T cell and humoral responses in mice. For this study, a tripartite CPP including a mucin 1 (MUC1) variable number of tandem repeat (VNTR) containing multiple T cell epitopes and tetanus toxoid universal T helper epitope peptide (tetCD4) was synthesised (AntpMAPMUC1tet) and immune responses investigated in mice. Mice vaccinated with AntpMAPMUC1tet + CpG show enhanced antigen-specific interferon-gamma (IFN-γ) and IL-4 T cell responses compared with AntpMAPMUC1tet vaccination alone and induced a Th1 response, characterised by a higher ratio of IgG2a antibody/IgG1 antibodies. Furthermore, vaccination generated long term MUC1-specific antibody and T cell responses and delayed growth of MUC1 tumours in mice. This data demonstrates the efficient delivery of branched multiple antigen peptides incorporating CPP and that the addition of CpG augments immune responses.
基于肽的癌症疫苗有许多优点,然而,为了优化这些免疫原,它们应该包含诱导 CD8 和 CD4 反应、抗体和长期免疫的肽表位。具有细胞质递送能力的细胞穿透肽 (CPP) 已被用于将抗原肽和蛋白质递送至抗原呈递细胞,以在小鼠中诱导细胞毒性 T 细胞、辅助 T 细胞和体液反应。在这项研究中,合成了一种包含粘蛋白 1 (MUC1) 可变数串联重复 (VNTR) 的三聚 CPP,其中包含多个 T 细胞表位和破伤风类毒素通用 T 辅助表位肽 (tetCD4)(AntpMAPMUC1tet),并在小鼠中研究了免疫反应。与单独接种 AntpMAPMUC1tet 相比,接种 AntpMAPMUC1tet + CpG 的小鼠表现出增强的抗原特异性干扰素-γ (IFN-γ) 和 IL-4 T 细胞反应,并诱导 Th1 反应,其特征是 IgG2a 抗体/IgG1 抗体的比值更高。此外,接种疫苗可产生长期的 MUC1 特异性抗体和 T 细胞反应,并延缓 MUC1 肿瘤在小鼠中的生长。该数据证明了包含 CPP 的分支多抗原肽的有效递呈,并且 CpG 的添加增强了免疫反应。