双功能HPV治疗性融合蛋白疫苗的抗癌作用实验研究
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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。
Human papillomaviruses (HPV), particularly HPV 16, is not only causally linked to cervical cancers but also play an important role in the development of other cancers.The prophylactic HPV vaccine cannot control already-established HPV infections, thus it is very important to develop the efficient and safe HPV therapeutic vaccine for the treatment of HPV-associated cancer. Protein-based HPV therapeutic vaccines are an appealing strategy because of their simplicity, safety and capacity for repeated administration. Researcher is focus on developing new approaches to further enhance vaccine efficacy. Heat shock proteins (HSP), including calreticulin (CRT) and HSP70, have been shown to act as potent immunoadjuvant to enhance antigen-specific anti-tumor immunity, respectively. Futhermore, Previous studies have shown that N domain CRT (NCRT) or C-terminal half of HSP70 (hsp) linked with HPV 16 E7 are capable of inducing potent antigen-specific CTL activity in experimental animal models.
Therefore, we have developed a recombinant NCRT/E7/hsp fusion protein to investigate the synergistic effects of NCRT and hsp for enhancing the potency of HPV16 E7 therapeutic vaccine and evaluated the immune responses induced by this fusion protein. In addition, given the potential benefit of NCRT inhibition of angiogenesis, we also determined the antiangiogenic effect of NCRT/E7/hsp fusion protein. Our results demonstrated that NCRT and hsp synergistically exhibited significant increases in E7-specific CD8~+ T cell responses and impressive antitumor effects against E7-expressing tumors. Furthermore, the NCRT/E7/hsp fusion protein also generates potent antiangiogenic effects. These results indicate that NCRT/E7/hsp fusion protein is a promising therapeutic vaccine for treatment of HPV-associated cancer through a combination of antigen-specific immunotherapy and antiangiogenesis, with possible therapeutic potential in clinical settings.
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。
Human papillomaviruses (HPV), particularly HPV 16, is not only causally linked to cervical cancers but also play an important role in the development of other cancers.The prophylactic HPV vaccine cannot control already-established HPV infections, thus it is very important to develop the efficient and safe HPV therapeutic vaccine for the treatment of HPV-associated cancer. Protein-based HPV therapeutic vaccines are an appealing strategy because of their simplicity, safety and capacity for repeated administration. Researcher is focus on developing new approaches to further enhance vaccine efficacy. Heat shock proteins (HSP), including calreticulin (CRT) and HSP70, have been shown to act as potent immunoadjuvant to enhance antigen-specific anti-tumor immunity, respectively. Futhermore, Previous studies have shown that N domain CRT (NCRT) or C-terminal half of HSP70 (hsp) linked with HPV 16 E7 are capable of inducing potent antigen-specific CTL activity in experimental animal models.
Therefore, we have developed a recombinant NCRT/E7/hsp fusion protein to investigate the synergistic effects of NCRT and hsp for enhancing the potency of HPV16 E7 therapeutic vaccine and evaluated the immune responses induced by this fusion protein. In addition, given the potential benefit of NCRT inhibition of angiogenesis, we also determined the antiangiogenic effect of NCRT/E7/hsp fusion protein. Our results demonstrated that NCRT and hsp synergistically exhibited significant increases in E7-specific CD8~+ T cell responses and impressive antitumor effects against E7-expressing tumors. Furthermore, the NCRT/E7/hsp fusion protein also generates potent antiangiogenic effects. These results indicate that NCRT/E7/hsp fusion protein is a promising therapeutic vaccine for treatment of HPV-associated cancer through a combination of antigen-specific immunotherapy and antiangiogenesis, with possible therapeutic potential in clinical settings.
引文
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