双功能HPV治疗性融合蛋白疫苗的抗癌作用实验研究
发布时间：2019-05-30 05:46
【摘要】： 人乳头瘤病毒(human papillomaviruse,HPV),特别是高危型HPV16,的持续感染与宫颈癌等多种肿瘤的发生与演进密切相关。由于预防性疫苗对已感染者无效,所以研制高效、安全的治疗性疫苗,对于HPV相关肿瘤的治疗将具有十分重要的意义。HPV治疗性蛋白疫苗由于具有安全、可重复用药和制备较简单等诸多优点,已经成为十分吸引人的策略。目前如何进一步提高疫苗的疗效仍是各国学者关注的热点。热休克蛋白(Heat shock proteins,HSP)家族,包括钙网蛋白(calreticulin,CRT)和HSP70,已被证明是一类强有力的免疫佐剂,它能够有效的增强抗原特异性的抗肿瘤免疫。以往的研究表明,钙网蛋白的N端(NCRT)或HSP70的C端的功能片段(hsp)与HPV16 E7联接后能诱导小鼠产生抗原特异性的CTL活性。 为此,本研究构建了NCRT/E7/hsp重组融合蛋白疫苗,利用NCRT抗肿瘤血管生成和抗原递呈作用联合hsp较强的佐剂功能协同增强HPV16 E7治疗性疫苗的效果。并评价此疫苗诱导的免疫反应和抗肿瘤血管生成作用。我们的研究结果表明,NCRT与hsp不仅能协同增强E7特异性的CD8~+T细胞免疫反应,还能产生更强的抗肿瘤效应。此外,NCRT/E7/hsp融合蛋白具有较强的抗血管生成作用,并能由此增强其抗肿瘤效应。到目前为此,尚未见到类似的报道。因此,NCRT/ET/hsp能通过抗原特异性的抗肿瘤免疫和抗肿瘤血管生成两方面功能更有效抑制HPV相关肿瘤,可能具有良好的应用前景。
[Abstract]:The persistent infection of human papillomavirus (human papillomaviruse,HPV), especially high-risk HPV16, is closely related to the occurrence and evolution of cervical cancer and other tumors. Because preventive vaccines are not effective for infected people, the development of efficient and safe therapeutic vaccines will be of great significance for the treatment of HPV-related tumors. HPV therapeutic protein vaccines are safe. Many advantages, such as reusable drug use and simple preparation, have become a very attractive strategy. At present, how to further improve the efficacy of vaccines is still the focus of attention of scholars all over the world. Heat shock protein (Heat shock proteins,HSP family, including calmodulin (calreticulin,CRT) and HSP70, has been proved to be a class of powerful immune adjuvants, which can effectively enhance antigen-specific antitumor immunity. Previous studies have shown that the N-terminal (NCRT) of calmodulin or the C-terminal functional fragment (hsp) of HSP70 can induce antigen-specific CTL activity in mice after ligating with HPV16 E7. In this study, NCRT/E7/hsp recombinant fusion protein vaccine was constructed, and the therapeutic effect of HPV16 E7 vaccine was enhanced by the combination of NCRT anti-tumor angiogenesis and antigen presentation combined with hsp adjuvant function. The immune response and anti-tumor angiogenesis induced by the vaccine were evaluated. Our results show that NCRT and hsp can not only enhance the specific CD8~ T cell immune response of E7, but also produce stronger antitumor effect. In addition, NCRT/E7/hsp fusion protein has strong anti-angiogenic effect and can enhance its anti-tumor effect. So far, no similar reports have been seen. Therefore, NCRT/ET/hsp can inhibit HPV-related tumors more effectively through antigen-specific anti-tumor immunity and anti-tumor angiogenesis, and may have a good application prospect.
【学位授予单位】：中国协和医科大学
【学位级别】：博士
【学位授予年份】：2008
【分类号】：R392;R730.5
[Abstract]:The persistent infection of human papillomavirus (human papillomaviruse,HPV), especially high-risk HPV16, is closely related to the occurrence and evolution of cervical cancer and other tumors. Because preventive vaccines are not effective for infected people, the development of efficient and safe therapeutic vaccines will be of great significance for the treatment of HPV-related tumors. HPV therapeutic protein vaccines are safe. Many advantages, such as reusable drug use and simple preparation, have become a very attractive strategy. At present, how to further improve the efficacy of vaccines is still the focus of attention of scholars all over the world. Heat shock protein (Heat shock proteins,HSP family, including calmodulin (calreticulin,CRT) and HSP70, has been proved to be a class of powerful immune adjuvants, which can effectively enhance antigen-specific antitumor immunity. Previous studies have shown that the N-terminal (NCRT) of calmodulin or the C-terminal functional fragment (hsp) of HSP70 can induce antigen-specific CTL activity in mice after ligating with HPV16 E7. In this study, NCRT/E7/hsp recombinant fusion protein vaccine was constructed, and the therapeutic effect of HPV16 E7 vaccine was enhanced by the combination of NCRT anti-tumor angiogenesis and antigen presentation combined with hsp adjuvant function. The immune response and anti-tumor angiogenesis induced by the vaccine were evaluated. Our results show that NCRT and hsp can not only enhance the specific CD8~ T cell immune response of E7, but also produce stronger antitumor effect. In addition, NCRT/E7/hsp fusion protein has strong anti-angiogenic effect and can enhance its anti-tumor effect. So far, no similar reports have been seen. Therefore, NCRT/ET/hsp can inhibit HPV-related tumors more effectively through antigen-specific anti-tumor immunity and anti-tumor angiogenesis, and may have a good application prospect.
【学位授予单位】：中国协和医科大学
【学位级别】：博士
【学位授予年份】：2008
【分类号】：R392;R730.5
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