Immunotherapy of a human papillomavirus (HPV) type 16 E7-expressing tumour by administration of fusion protein comprising Mycobacterium bovis bacille Calmette-Guerin (BCG) hsp65 and HPV16 E7
Immunotherapy of a human papillomavirus (HPV) type 16 E7-expressing tumour by administration of fusion protein comprising Mycobacterium bovis bacille Calmette-Guerin (BCG) hsp65 and HPV16 E7
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DOI：
10.1046/j.1365-2249.2000.01293.x
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发表时间：
2000-08-01
影响因子：
4.6
通讯作者：
Mizzen, LA
中科院分区：
文献类型：
--
作者：
Chu, NR;Wu, HB;Mizzen, LA
人乳头瘤病毒16型（HPV 16）感染与宫颈和肛门发育不良和癌症的发生有关。持续感染的一个标志是宫颈上皮细胞中病毒E7蛋白的合成。E7在异型增生和转化细胞中的表达及其作为外源抗原被免疫系统识别，使其成为免疫治疗的理想靶点。利用表达E7的鼠肿瘤细胞系TC-1作为宫颈癌的模型，已经开发了基于施用包含连接至HPV 16 E7（hspE 7）的牛分枝杆菌BCG热休克蛋白（hsp）65的无促凝剂融合蛋白的免疫疗法。数据显示，用hspE 7预防性免疫保护小鼠免受TC-1细胞的攻击，并且这些无肿瘤动物也受到保护免受TC-1细胞的再攻击。此外，用hspE 7进行治疗性免疫诱导可触知肿瘤的消退，赋予针对肿瘤再攻击的保护，并且与长期存活（> 253天）相关。体外分析表明，hspE 7免疫导致诱导的Th 1样细胞介导的免疫应答的基础上分泌的细胞因子的模式和抗原回忆后的细胞溶解活性的存在。使用具有CD 8或MHC II类靶向突变或CD 8或CD 4淋巴细胞亚群耗竭的小鼠的体内研究表明，治疗性hspE 7免疫后的肿瘤消退是CD 8依赖性和CD 4非依赖性的。这些研究扩展了以前的观察，诱导细胞毒性T淋巴细胞的热休克蛋白融合蛋白，并与临床应用的热休克蛋白E7作为一种免疫疗法的人宫颈和肛门异型增生和癌症是一致的。
Human papillomavirus type 16 (HPV16) infection has been linked to the development of cervical and anal dysplasia and cancer. One hallmark of persistent infection is the synthesis of the viral E7 protein in cervical epithelial cells. The expression of E7 in dysplastic and transformed cells and its recognition by the immune system as a foreign antigen make it an ideal target for immunotherapy. Utilizing the E7-expressing murine tumour cell line, TC-1, as a model of cervical carcinoma, an immunotherapy based on the administration of an adjuvant-free fusion protein comprising Mycobacterium bovis BCG heat shock protein (hsp)65 linked to HPV16 E7 (hspE7) has been developed. The data show that prophylactic immunization with hspE7 protects mice against challenge with TC-1 cells and that these tumour-free animals are also protected against re-challenge with TC-1 cells. In addition, therapeutic immunization with hspE7 induces regression of palpable tumours, confers protection against tumour re-challenge and is associated with long-term survival (> 253 days). In vitro analyses indicated that immunization with hspE7 leads to the induction of a Th1-like cell-mediated immune response based on the pattern of secreted cytokines and the presence of cytolytic activity following antigenic recall. In vivo studies using mice with targeted mutations in CD8 or MHC class II or depleted of CD8 or CD4 lymphocyte subsets demonstrate that tumour regression following therapeutic hspE7 immunization is CD8-dependent and CD4-independent. These studies extend previous observations on the induction of cytotoxic T lymphocytes by hsp fusion proteins and are consistent with the clinical application of hspE7 as an immunotherapy for human cervical and anal dysplasia and cancer.