p53及B7重组痘苗病毒抗肿瘤的实验研究

Antitumor Responses Induced by Recombinant Vaccinia Viruses Expressing p53 and B7

目的：探索点突变 ｐ５３重组痘苗病毒诱导的抗瘤免疫反应及 Ｂ７对其加强作用，为重组抗原疫苗用于肿瘤免疫治疗提供实验依据。方法：选择人 １３５位 Ｃｙｓ→Ｔｙｒ点突变ｐ５３作为肿瘤相关抗原模型，观察以表达该点突变 ｐ５３的重组痘苗病毒ｒＶＶ－ｐ５３ＦＬ单独和联合表达 Ｂ７的重组痘苗病毒 ｒＶＶ－Ｂ７所诱导的 ＣＴＬ及对荷瘤小鼠的免疫保护和治疗作用。结果：以 ｒＶＶ－ｐ５３ＦＬ经静脉免疫 ＢＡＬＢ／ｃ小鼠能够诱导以 ＣＤＳ＋ Ｔ细胞为主的特异性 ＣＴＬ。ｒＶＶ－ｐ５３ＦＬ能够保护部分小鼠免遭肿瘤细胞的攻击。以ｒＶＶ－ｐ５３ＦＬ治疗荷瘤小鼠，可显著延长小鼠平均存活期。ｒＶＶ－Ｂ７与ｒＶＶ－ｐ５３ＦＬ以１：１的比例混合接种可部分加强ｒｖｖ－ｐ５３ＦＬ的治疗作用。结论：肿瘤细胞内过度表达的突变Ｐ５３蛋白可作为ＣＴＬ识别和攻击的靶抗原，以突变Ｐ５３蛋白作为肿瘤抗原的疫苗可诱导机体产生 ｐ５３特异性的抗瘤免疫反应。共刺激分子 Ｂ７可加强肿瘤抗原诱导的抗瘤免疫反应。

Objective: This study was aimed to explore antitumor responses induced by recombinant vaccinia viruses expressing a point mutant p53 (rVV-p53FL) and enhancive effects of recombinant vaccinia viruses expressing costimulatory molecule B7 (rVV-B7). Methods: A 135 Cys to Tyr point mutant p53 protein was used as the model of tumor associated antigen. rVV-of3FL and rVV-B7 were used as vaccines to test their induction of CTLs and antitumor immunity. Results: Immunization BABL/c mice with rVV-p53FL could elicited specific CD8+ CTLs that could effecively lyse P815-mp53 cells, a transfectant of the murine P815 mastocytoma containing the mutant p53 gene. Treatment with rVV-p53FL could survive a part of mice challenged with 1 × 106 P815-mp53. Treatment with rVV-p53FL could significantly prolong survival of tumor-bearing force. Admixture at 1: 1 ratio of rVV-p53FL and rVV-B7 could enhance therapeutic antitumor effects of rVV-p53FL. ~Conclusion: Mutant P53 over-expressed in tumor cells can render cells targets for specific CTLs generated by immunization with mutant p53 protein based vaccine. Costimulatory molecule H7 can enhance tumor-associated antigen inducing antitumor responses.