Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
Cancer Res. 2010 Jan 1;70(1):119-28. doi: 10.1158/0008-5472.CAN-09-2554.
Immune tolerance to tumor-associated self-antigens poses a major challenge in the ability to mount an effective cancer vaccine response. To overcome immune tolerance to HER-2, we formulated DNA vaccines that express both human HER-2 and heterologous rat Neu sequences in separate plasmids or as single hybrid constructs that encode HER-2/Neu fusion proteins. Candidate vaccines were tested in Her-2 transgenic (Tg) mice of BALB/c (BALB), BALB/cxC57BL/6 F1 (F1), or C57BL/6 (B6) background, which exhibit decreasing immune responsiveness to HER-2. Analysis of various cocktails or hybrid vaccines defined a requirement for particular combination of HER/2/Neu sequences to effectively prime immune effector cells in HER-2 Tg mice. In B6 HER-2 Tg mice, rejection of HER-2-positive tumors protected mice from HER-2-negative tumors, providing evidence of epitope spreading. Our findings show that a strategy of combining heterologous antigen with self-antigens could produce a potent DNA vaccine that may be applicable to other tumor-associated antigens.
肿瘤相关自身抗原的免疫耐受是机体产生有效癌症疫苗反应的主要挑战。为了克服对 HER-2 的免疫耐受，我们构建了表达人 HER-2 和异体大鼠 Neu 序列的 DNA 疫苗，分别在质粒中表达或编码 HER-2/Neu 融合蛋白的单个杂交构建体中表达。候选疫苗在具有 BALB/c（BALB）、BALB/cxC57BL/6 F1（F1）或 C57BL/6（B6）背景的 Her-2 转基因（Tg）小鼠中进行了测试，这些小鼠对 HER-2 的免疫反应逐渐降低。对各种鸡尾酒或杂交疫苗的分析确定了有效刺激 HER-2 Tg 小鼠免疫效应细胞所需的 HER/2/Neu 序列的特定组合。在 B6 HER-2 Tg 小鼠中，对 HER-2 阳性肿瘤的排斥反应保护小鼠免受 HER-2 阴性肿瘤的侵害，这提供了表位扩展的证据。我们的研究结果表明，将异源抗原与自身抗原结合的策略可以产生一种有效的 DNA 疫苗，可能适用于其他肿瘤相关抗原。
