Department of Otolaryngology, University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, USA.
Cancer Immunol Immunother. 2010 Oct;59(10):1561-8. doi: 10.1007/s00262-010-0886-1. Epub 2010 Jun 25.
The TP53 tumor suppressor gene contains a well-studied polymorphism that encodes either proline (P) or arginine (R) at codon 72, and over half of the world's population is homozygous for R at this codon. The wild-type sequence (wt) p53 peptide, p53(65-73), has been identified as a CD8+ T cell-defined tumor antigen for use in broadly applicable cancer vaccines. However, depending on the TP53 codon 72 polymorphism of the recipient, the induced responses to the peptides incorporating R (p53(72R)) or P (p53(72P)) can be "self" or "non-self." Thus, we sought to determine which wt p53(65-73) peptide should be used in wt p53-based cancer vaccines. Despite similar predicted HLA-A2-binding affinities, the p53(72P) peptide was more efficient than the p53(72R) peptide in HLA-A2 stabilization assays. In vitro stimulation (IVS) of CD8+ T cells obtained from healthy HLA-A2(+) donors with these two peptides led to the generation of CD8+ T cell effectors in one-third of the samples tested, at a frequency similar to the responsiveness to other wt p53 peptides. Interestingly, regardless of their p53 codon 72 genotype, CD8+ T cells stimulated with either p53(72P) or p53(72R) peptide were cross-reactive against T2 cells pulsed with either peptide, as well as HLA-A2(+) head and neck cancer (HNC) cell lines presenting p53(72P) and/or p53(72R) peptides for T cell recognition. Therefore, the cross-reactivity of CD8+ T cells for the polymorphic wt p53(65-73) peptides, irrespective of their p53 codon 72 polymorphism, suggests that employing either peptide in wt p53-based vaccines can result in efficient targeting of this epitope.
TP53 肿瘤抑制基因包含一个经过充分研究的多态性，该多态性在密码子 72 处编码脯氨酸（P）或精氨酸（R），世界上超过一半的人口在这个密码子处纯合为 R。野生型序列（wt）p53 肽，p53（65-73），已被鉴定为用于广泛应用的癌症疫苗的 CD8+T 细胞定义的肿瘤抗原。然而，根据受体的 TP53 密码子 72 多态性，对包含 R（p53（72R））或 P（p53（72P））的肽的诱导反应可以是“自身”或“非自身”。因此，我们试图确定在 wt p53 基癌症疫苗中应使用哪种 wt p53（65-73）肽。尽管具有相似的预测 HLA-A2 结合亲和力，但 p53（72P）肽在 HLA-A2 稳定测定中比 p53（72R）肽更有效。用这两种肽体外刺激（IVS）从健康 HLA-A2（+）供体中获得的 CD8+T 细胞，导致在三分之一的测试样本中产生 CD8+T 细胞效应物，其频率与对其他 wt p53 肽的反应性相似。有趣的是，无论其 p53 密码子 72 基因型如何，用 p53（72P）或 p53（72R）肽刺激的 CD8+T 细胞都可与用任一种肽脉冲的 T2 细胞以及呈递 p53（72P）和/或 p53（72R）肽的 HLA-A2（+）头颈部癌症（HNC）细胞系发生交叉反应，以识别 T 细胞。因此，不论其 p53 密码子 72 多态性如何，CD8+T 细胞对多态性 wt p53（65-73）肽的交叉反应性表明，在 wt p53 基疫苗中使用任一种肽都可以有效地靶向该表位。
