Vaccine-mediated immunotherapy directed against a transcription factor driving the metastatic process.
Vaccine-mediated immunotherapy directed against a transcription factor driving the metastatic process.
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DOI：
10.1158/0008-5472.can-13-2045
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发表时间：
2014-04-01
期刊：
影响因子：
11.2
通讯作者：
Hodge JW
中科院分区：
文献类型：
--
作者：
Ardiani A;Gameiro SR;Palena C;Hamilton DH;Kwilas A;King TH;Schlom J;Hodge JW
大量研究表明，上皮细胞向间质细胞转化（EMT）过程参与实体瘤的进展、转移和耐药性。几种转录因子被认为是EMT和转移进展的驱动因子，包括Twist。Twist的过表达已被证明与许多癌症和其他肿瘤类型的不良预后和耐药性相关。Twist在实验性癌症转移中的作用主要在4T1乳腺肿瘤模型中进行了研究，其中体外Twist的沉默已显示出极大地降低了体内转移扩散。转录因子如Twist通常被认为是“不可用药的”，这是由于它们的核位置和缺乏用于紧密结合小分子抑制剂的特异性沟。靶向驱动转移过程的转录因子的药物疗法的替代方法是T细胞介导的免疫疗法。先前已表征的治疗性疫苗平台由能够表达肿瘤相关抗原蛋白的热灭活重组酿酒酵母（酵母）组成。我们在这里报告的构建和表征的重组酵母表达的整个Twist蛋白，这是能够在体内诱导CD8+和CD4+ Twist特异性T细胞反应。小鼠的疫苗接种减小了原发移植的4T1肿瘤的大小，并且对相同小鼠的肺转移具有甚至更大的抗肿瘤作用，这依赖于Twist特异性CD8+ T细胞。这些研究为疫苗诱导的T细胞介导的转录因子治疗提供了理论基础，这些转录因子参与驱动转移过程。
Numerous reports have now demonstrated that the epithelial-to-mesenchymal transition (EMT) process is involved in solid tumor progression, metastasis, and drug resistance. Several transcription factors have been implicated as drivers of EMT and metastatic progression, including Twist. Overexpression of Twist has been shown to be associated with poor prognosis and drug resistance for many carcinomas and other tumor types. The role of Twist in experimental cancer metastases has been principally studied in the 4T1 mammary tumor model, where silencing of Twist in vitro has been shown to greatly reduce in-vivo metastatic spread. Transcription factors such as Twist are generally believed to be “undruggable” due to their nuclear location and lack of a specific groove for tight binding of a small molecule inhibitor. An alternative approach to drug therapy targeting transcription factors driving the metastatic process is T-cell–mediated immunotherapy. A therapeutic vaccine platform that has been previously characterized consists of heat-killed recombinant Saccharomyces cerevisiae (yeast) capable of expressing tumor-associated antigen protein. We report here the construction and characterization of a recombinant yeast expressing the entire Twist protein, which is capable of inducing both CD8+ and CD4+ Twist-specific T-cell responses in vivo. Vaccination of mice reduced the size of primary transplanted 4T1 tumors and had an even greater anti-tumor effect on lung metastases of the same mice, which was dependent on Twist-specific CD8+ T cells. These studies provide the rationale for vaccine-induced T-cell–mediated therapy of transcription factors involved in driving the metastatic process.