Toes R E, Blom R J, Offringa R, Kast W M, Melief C J
Department of Immunohematology and Blood Bank, University Hospital, Leiden, The Netherlands.
J Immunol. 1996 May 15;156(10):3911-8.
CTL can play an important role in the defense against tumors. Protective CTL-mediated immunity can be established in animal tumor models after vaccination with synthetic peptides representing CTL epitopes. We now report that immunization with synthetic peptides can also lead to CTL tolerance associated with the inability to reject tumors. B6 tumor cells transformed by the human adenovirus early region 1 (Ad5E1) present an Ad5E1A- and an Ad5E1B-encoded CTL epitope to the immune system. CTL clones directed against either of these epitopes are able to eradicate established Ad5E1-induced tumors, showing that these CTL epitopes are targets of CTL that can mediate tumor regression. Here, we show that protective immunity against Ad5E1-expressing tumor cells can be established by immunization with Ad5E1-transformed cells and with an adenovirus vector containing the Ad5E1 region. Protective immunity, in either case, is associated with specific CTL memory. To test whether vaccination with synthetic peptides leads to protection against Ad5E1-expressing tumor cells, we vaccinated mice s.c. with a low dose of the Ad5E1B peptide. This peptide was chosen because the CTL response against the Ad5E1B-encoded CTL epitope contributes most to the antitumor response in B6 mice after vaccination with Ad5E1-transformed cells. Ad5E1B peptide-vaccinated mice were not protected against the outgrowth of Ad5E1-expressing tumor cells, but instead were no longer able to reject a tumor inoculum that was rejected by nonvaccinated mice. Moreover, the protection induced by tumor cell vaccination against Ad5E1B-expressing tumors was gone when the Ad5E1B-encoded CTL epitope was injected a few days before tumor challenge. This is associated with peptide-induced tolerance of Ad5E1B-specific CTL activity. These findings are relevant for the design of therapeutic approaches against both malignancies and T cell-mediated autoimmune diseases.
细胞毒性T淋巴细胞（CTL）在抗肿瘤防御中可发挥重要作用。在用代表CTL表位的合成肽进行疫苗接种后，可在动物肿瘤模型中建立起具有保护作用的CTL介导的免疫。我们现在报告，用合成肽进行免疫也可导致与无法排斥肿瘤相关的CTL耐受。由人腺病毒早期区域1（Ad5E1）转化的B6肿瘤细胞向免疫系统呈递一个Ad5E1A编码的和一个Ad5E1B编码的CTL表位。针对这些表位中任何一个的CTL克隆都能够根除已形成的Ad5E1诱导的肿瘤，这表明这些CTL表位是能够介导肿瘤消退的CTL的靶标。在此，我们表明，通过用Ad5E1转化的细胞和含有Ad5E1区域的腺病毒载体进行免疫，可建立针对表达Ad5E1的肿瘤细胞的保护性免疫。在这两种情况下，保护性免疫均与特异性CTL记忆相关。为了测试用合成肽进行疫苗接种是否能产生针对表达Ad5E1的肿瘤细胞的保护作用，我们用低剂量的Ad5E1B肽对小鼠进行皮下接种。选择该肽是因为在用Ad5E1转化的细胞进行疫苗接种后，针对Ad5E1B编码的CTL表位的CTL反应对B6小鼠的抗肿瘤反应贡献最大。接种Ad5E1B肽的小鼠对表达Ad5E1的肿瘤细胞的生长没有得到保护，相反，它们不再能够排斥未接种小鼠能够排斥的肿瘤接种物。此外，当在肿瘤攻击前几天注射Ad5E1B编码的CTL表位时，肿瘤细胞疫苗接种诱导的针对表达Ad5E1B的肿瘤的保护作用消失了。这与肽诱导的Ad5E1B特异性CTL活性耐受有关。这些发现对于针对恶性肿瘤和T细胞介导的自身免疫性疾病的治疗方法设计具有重要意义。
