Elicitation of T cell responses to histologically unrelated tumors by immunization with the novel cancer-testis antigen, brother of the regulator of imprinted sites
Elicitation of T cell responses to histologically unrelated tumors by immunization with the novel cancer-testis antigen, brother of the regulator of imprinted sites
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DOI：
10.4049/jimmunol.178.1.566
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发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
Agadjanyan, Michael G.
中科院分区：
文献类型：
--
作者：
Ghochikyan, Anahit;Mkrtichyan, Mikayel;Agadjanyan, Michael G.
印迹位点调节因子兄弟(Boris)以前被描述为表观遗传重编程的转录因子，其表达严格限于成人睾丸的生殖细胞，但在绝大多数肿瘤细胞中被异常激活。考虑到Boris在癌症发生中的关键作用以及其表达模式可能排除胸腺耐受的事实，我们使用Boris分子的非DNA结合版本制备了基于DNA和蛋白质的小鼠Boris抗肿瘤疫苗。鲍里斯作为疫苗抗原的临床应用需要满足某些安全问题。具体地说，服用功能性Boris蛋白可能会带来Boris加速癌症进展的风险。为了缓解这种安全问题，我们开发了基于缺少DNA结合锌指结构域的Boris分子的疫苗。为了增强抗Boris细胞免疫反应，我们使用了标准的分子佐剂方法。它包括编码小鼠IL-12和IL-18的DNA疫苗和用于蛋白质疫苗的传统Th1型佐剂Quil A。DNA疫苗和蛋白质疫苗分别以Th1和Th2细胞因子诱导抗原特异性的CD4(+)T细胞增殖。基于蛋白质而不是基于DNA的鲍里斯疫苗在免疫动物中诱导了显著水平的抗体产生。重要的是，在基于DNA而不是基于蛋白质的Boris疫苗免疫后，产生了强大的抗癌CD8(+)细胞毒性淋巴细胞。在包括乳腺癌、胶质瘤、白血病和肥大细胞瘤在内的多种不同的小鼠癌症中观察到了这些细胞溶解反应。
Brother of the regulator of imprinted sites (BORIS) was previously described as a transcription factor for epigenetic reprogramming the expression of which is strictly confined to germ cells of adult testes but is aberrantly activated in the vast majority of neoplastic cells. Considering the critical role of BORIS in cancerogenesis and the fact that its expression pattern may preclude thymic tolerance, we generated DNA- and protein-based mouse BORIS antitumor vaccines using a non-DNA-binding version of the BORIS molecule. Clinical use of BORIS as a vaccine Ag would require that certain safety concerns be met. Specifically, administration of the functional BORIS protein would hypothetically pose a risk of BORIS accelerating the progression of cancer. To alleviate such safety concerns, we have developed vaccines based on the BORIS molecule lacking the DNA-binding zinc fingers domain. To enhance anti-BORIS cellular immune responses, we used a standard molecular adjuvant approach. It consisted of plasmids encoding murine IL-12 and IL-18 for a DNA-based vaccine and conventional Th1 type adjuvant, Quil A, for a protein-based vaccine. Both DNA- and protein-based vaccines induced Ag-specific CD4(+) T cell proliferation with Th1 and Th2 cytokine profiles, respectively. Protein-based, but not DNA-based, BORIS vaccine induced a significant level of Ab production in immunized animals. Importantly, potent anticancer CD8(+)-cytotoxic lymphocytes were generated after immunization with the DNA-based, but not protein-based, BORIS vaccine. These cytolytic responses were observed across a wide range of different mouse cancers including mammary adenocarcinoma, glioma, leukemia, and mastocytoma.