Loukinov Dmitri, Ghochikyan Anahit, Mkrtichyan Mikayel, Ichim Thomas E, Lobanenkov Victor V, Cribbs David H, Agadjanyan Michael G
National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
J Cell Biochem. 2006 Aug 1;98(5):1037-43. doi: 10.1002/jcb.20953.
Cancer testis (CT) antigens are promising candidates for tumor vaccines due to their immunogenicity and tissue-restricted expression. Recently, we identified a novel cancer testis gene, BORIS, whose expression is restricted to male testis after puberty and is strictly absent in non-malignant female tissue. BORIS encodes a DNA-binding protein that shares 11 zing finger (ZF) with transcription factor CTCF and differs at the N- and C-termini. CTCF has been implicated in epigenetic regulation of imprinting, X chromosome inactivation, repression, and activation of cancer testis antigens. BORIS expression has been documented in cancers of diverse histological origin, including, but not limited to breast, prostate, ovary, gastric, liver, endometrial, glia, colon, and esophagus. Interestingly, BORIS induces demethylation and subsequent expression of many cancer-testis genes, including MAGE-A1 and NY-ESO-1, indicating that it is expressed very early in malignancy and might be an attractive candidate for immunotherapy. In this study we tested BORIS as a vaccine in a very aggressive, highly metastatic, and poorly immunogenic murine model of mammary carcinoma. Immunizations with a DNA encoding the mutant form of murine BORIS antigen (pmBORIS lacking DNA-binding function) significantly prolonged survival, and inhibited tumor growth in BALB/c mice inoculated with 4T1 cells. Priming with pmBORIS mixed with molecular adjuvant and boosting with adenoviral vector expressing mBORIS was generally more effective, suggesting that the vaccination protocol could be further optimized. This is the first report demonstrating the feasibility of vaccination with a cancer associated epigenetic regulator for the induction of tumor inhibition.
癌胚抗原（CT）因其免疫原性和组织限制性表达，是肿瘤疫苗的理想候选物。最近，我们鉴定出一个新的癌胚基因BORIS，其表达在青春期后仅限于男性睾丸，在非恶性女性组织中则完全不存在。BORIS编码一种DNA结合蛋白，与转录因子CTCF共享11个锌指（ZF），但在N端和C端有所不同。CTCF参与了印记、X染色体失活、癌胚抗原的抑制和激活的表观遗传调控。BORIS的表达已在多种组织学来源的癌症中得到证实，包括但不限于乳腺癌、前列腺癌、卵巢癌、胃癌、肝癌、子宫内膜癌、神经胶质瘤、结肠癌和食管癌。有趣的是，BORIS可诱导许多癌胚基因的去甲基化及随后的表达，包括MAGE-A1和NY-ESO-1，这表明它在恶性肿瘤早期就已表达，可能是免疫治疗的一个有吸引力的候选物。在本研究中，我们在一种侵袭性很强、高度转移且免疫原性很差的小鼠乳腺癌模型中测试了BORIS作为疫苗的效果。用编码鼠BORIS抗原突变形式（缺乏DNA结合功能的pmBORIS）的DNA进行免疫接种，可显著延长BALB/c小鼠接种4T1细胞后的生存期，并抑制肿瘤生长。用pmBORIS与分子佐剂混合进行初免，并用表达mBORIS的腺病毒载体进行加强免疫通常更有效，这表明疫苗接种方案可进一步优化。这是第一份证明用与癌症相关的表观遗传调节因子进行疫苗接种以诱导肿瘤抑制的可行性的报告。
