Effect of human papillomavirus-16 infection on CD8+ T-cell recognition of a wild-type sequence p53264-272 peptide in patients with squamous cell carcinoma of the head and neck
Effect of human papillomavirus-16 infection on CD8+ T-cell recognition of a wild-type sequence p53264-272 peptide in patients with squamous cell carcinoma of the head and neck
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DOI：
10.1158/1078-0432.ccr-04-0672
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发表时间：
2004-10-15
影响因子：
11.5
通讯作者：
Ferris, RL
中科院分区：
文献类型：
--
作者：
Sirianni, N;Ha, PK;Ferris, RL
目的：野生型序列（wt）p53肽是广泛适用的癌症疫苗的有吸引力的候选物，目前主要考虑用于肿瘤过表达p53的患者。然而，存在这样的情况，其中增加的p53降解可能导致p53衍生肽的可观呈递，尽管p53表达低。头颈部鳞状细胞癌与致癌的人乳头瘤病毒（HPV）亚型有关，HPV亚型通过蛋白酶体降解而破坏p53。实验设计：我们测试了HPV感染与增强的p53蛋白抗原性的相关性，并假设去除HPV-16（+）肿瘤与增强的p53（264）-（272）肽呈递可能导致体内对该肽特异性的T细胞下降。使用二聚体HLA：肽复合物，在肿瘤切除前和肿瘤切除后6个月，在15名头颈癌患者中离体测量对HLA A*0201：p53（264）-（272）复合物特异性的T细胞的循环频率。HPV-16 E6表达增强了CD 8 + T细胞对HPV-16（-）头颈部鳞状细胞癌呈递的HLA A*0201限制性wt p53（264）-（272）肽的识别，有时超过自然转化的、表达HPV-16（+）wt p53的头颈部鳞状细胞癌细胞系。在HPV-16肿瘤患者中，肿瘤切除后wt p53（264）-（272）特异性T细胞的频率基本保持不变。然而，HPV-16（+）患者术后抗p53（264-272）T细胞频率显着下降（P < 0.005）。结论：HPV相关头颈部鳞状细胞癌的识别似乎与wt p53特异性T细胞水平相关，与p53表达呈负相关。除了病毒基因产物外，p53肽可能是头颈部鳞状细胞癌免疫治疗的有用肿瘤抗原。
Purpose: Wild-type sequence (wt) p53 peptides are attractive candidates for broadly applicable cancer vaccines, currently considered primarily for patients whose tumors overexpress p53. Circumstances exist, however, where increased p53 degradation may result in appreciable presentation of p53-derived peptides, despite low p53 expression. Squamous cell carcinoma of the head and neck is associated with oncogenic human papillomavirus (HPV) subtypes, which inactivate p53 through proteasomal degradation. The criterion of p53 overexpression would exclude these individuals from wt p53-based immunotherapy.Experimental Design: We tested the correlation of HPV infection with enhanced antigenicity of the p53 protein and postulated that removal of HPV-16(+) tumors with enhanced p53(264)-(272) peptide presentation might lead to a drop in T cells specific for this peptide in vivo. Circulating frequencies of T cells specific for the HLA A*0201:p53(264)-(272) complex were measured ex vivo using dimeric HLA:peptide complexes in 15 head and neck cancer patients before and 6 months after tumor excision.Results: CD8+ T-cell recognition of HLA A*0201-restricted wt p53(264)-(272) peptide presented by HPV-16(-) squamous cell carcinoma of the head and neck lines was enhanced by HPV-16 E6 expression, sometimes exceeding that of a naturally transformed, HPV-16(+) wt p53 expressing squamous cell carcinoma of the head and neck cell line. In patients with HPV-16- tumors, the frequency of wt p53(264)-(272)-specific T cells remained largely unchanged after tumor removal. However, a significant decline in frequency of anti-p53(264-272) T cells was observed postoperatively in HPV-16(+) patients (P < 0.005).Conclusions: Recognition of HPV-associated squamous cell carcinoma of the head and neck appears associated with levels of wt p53-specific T cells and inversely with p53 expression. p53 peptides may be useful tumor antigens for squamous cell carcinoma of the head and neck immunotherapy in addition to viral gene products.