CD8+T cell recognition of polymorphic wild-type sequence p5365-73 peptides in squamous cell carcinoma of the head and neck
CD8+T cell recognition of polymorphic wild-type sequence p5365-73 peptides in squamous cell carcinoma of the head and neck
复制标题
DOI：
10.1007/s00262-010-0886-1
复制
发表时间：
2010-10-01
影响因子：
5.8
通讯作者：
Ferris, Robert L.
中科院分区：
文献类型：
--
作者：
Andrade Filho, Pedro A.;Ito, Daisuke;Ferris, Robert L.
TP 53肿瘤抑制基因包含一个被充分研究的多态性，其在密码子72处编码脯氨酸（P）或精氨酸（R），并且超过一半的世界人口在该密码子处为R纯合。野生型序列（wt）p53肽p53（65-73）已被鉴定为用于广泛适用的癌症疫苗的CD 8 + T细胞定义的肿瘤抗原。然而，根据受体的TP 53密码子72多态性，对掺入R（p53（72 R））或P（p53（72 P））的肽的诱导应答可以是“自身的”或“非自身的”。因此，我们试图确定哪种wt p53（65-73）肽应该用于基于wt p53的癌症疫苗。尽管预测的HLA-A2结合亲和力相似，但在HLA-A2稳定化测定中，p53（72 P）肽比p53（72 R）肽更有效。用这两种肽体外刺激（IVS）从健康HLA-A2（+）供体获得的CD 8 + T细胞导致在三分之一的测试样品中产生CD 8 + T细胞效应物，其频率与对其他wt p53肽的响应性相似。有趣的是，无论其p53密码子72基因型如何，用p53（72 P）或p53（72 R）肽刺激的CD 8 + T细胞与用任一肽脉冲的T2细胞以及呈递用于T细胞识别的p53（72 P）和/或p53（72 R）肽的HLA-A2（+）头颈癌（HNC）细胞系交叉反应。因此，CD 8 + T细胞对多态性wt p53（65-73）肽的交叉反应性，与它们的p53密码子72多态性无关，表明在基于wt p53的疫苗中使用任一肽可以导致有效靶向该表位。
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.