Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck
Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck
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DOI：
10.1158/0008-5472.can-05-0772
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发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Ferris, RL
中科院分区：
文献类型：
--
作者：
Albers, A;Abe, K;Ferris, RL
人乳头瘤病毒（HPV）相关的头颈部鳞状细胞癌（SCCHN）似乎是癌症疫苗接种的合适目标。hpv编码的致癌蛋白，如E7，是有希望的肿瘤特异性抗原，是肿瘤生长所必需的。由于很少有免疫学研究分析了该SCCHN患者亚群中内源性hpv特异性免疫反应，因此我们研究了荷瘤人白细胞抗原(HLA)- a *0201(+) SCCHN患者中针对HPV-16 E7（11-20）或E7（86-93）的t细胞频率，其肿瘤为HPV-16（+）或HPV-16（-）。在HPV-16+ SCCHN患者中，与HPV-16患者或健康志愿者相比，抗任一肽的T细胞频率显著升高（P < 0.005）。四聚体（+）T细胞显示终末分化表型(CD45RA（+)CCR7(-)）和CD107a脱粒染色水平升高。尽管可以检测到限制性HLA I类等位基因的表达，但通过体外刺激健康供体外周血单个核细胞获得的HLA- a *0201- e7(11-20)-或RLAA-0201-E7（16-91）特异性CTL仅识别经ifn - γ预处理的自然hpv -16转化的HLA- a *0201(+) SCCHN细胞系。该细胞系很少或不表达LMP2、TAP1和tapasin，这是HLA I类抗原加工机制的关键成分，它们在ifn - γ处理下被上调。HPV-16+ SCCHN肿瘤的免疫组化显示，与邻近正常鳞状上皮相比，这些抗原加工机械成分在肿瘤体内下调。因此，对HPV-16 E7的免疫与HPV-16感染的存在和E7衍生肽在SCCHN细胞上的呈现有关，这显示了免疫逃逸的证据。这些发现支持进一步开发e7特异性免疫疗法和策略，以上调hpv相关SCCHN的抗原加工机械成分。
Human papillomavirus (HPV)-associated squamous cell carcinoma of the head and neck (SCCHN) seems to be a suitable target for cancer vaccination. HPV-encoded oncogenic proteins, such as E7, are promising tumor-specific antigens and are obligatory for tumor growth. Because few immunologic studies have analyzed the endogenous HPV-specific immune response in this subset of SCCHN patients, we studied T-cell frequencies against HPV-16 E7(11-20) or E7(86-93) in tumor-bearing, human leukocyte antigen (HLA)-A*0201(+) SCCHN patients, whose tumors were either HPV-16(+) or HPV-16(-). In HPV-16+ SCCHN patients, frequencies of T cells against either peptide were significantly elevated (P < 0.005) compared with HPV-16- patients or healthy volunteers. Tetramer(+) T cells showed evidence of terminally differentiated phenotype (CD45RA(+)CCR7(-)) and an elevated level of CD107a staining for degranulation. Despite detectable expression of the restricting HLA class I allele, HLA-A*0201-E7(11-20)- or RLAA-0201-E7(16-91)-specific CTL obtained by in vitro stimulation of healthy donor peripheral blood mononuclear cells only recognize a naturally HPV-16-transformed, HLA-A*0201(+) SCCHN cell line after pretreatment with IFN-gamma. This cell line had little or no expression of LMP2, TAP1, and tapasin, critical components of the HLA class I antigen-processing machinery, which were up-regulated by IFN-gamma treatment. Immunohistochemistry of HPV-16+ SCCHN tumors showed that these antigen-processing machinery components are down-regulated in tumors in vivo compared with adjacent normal squamous epithelium. Thus, immunity to HPV-16 E7 is associated with the presence of HPV-16 infection and presentation of E7-derived peptides on SCCHN cells, which show evidence of immune escape. These findings support further development of E7-specific immunotherapy and strategies for up-regulation of antigen-processing machinery components in HPV-associated SCCHN.