The androgen receptor: a biologically relevant vaccine target for the treatment of prostate cancer.
The androgen receptor: a biologically relevant vaccine target for the treatment of prostate cancer.
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DOI：
10.1007/s00262-012-1363-9
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发表时间：
2013-03
影响因子：
5.8
通讯作者：
McNeel, Douglas G.
中科院分区：
文献类型：
--
作者：
Olson, Brian M.;Johnson, Laura E.;McNeel, Douglas G.
雄激素受体（AR）在前列腺癌的发生和发展中起着至关重要的作用。然而，尽管它长期以来一直是转移性前列腺癌治疗的主要分子靶点，但尚未被作为免疫治疗靶点进行探索。特别是，AR配体结合域（LBD）是一个潜在的有吸引力的靶点，因为它在人类以及多个物种中具有相同的序列，为临床前评估提供了合理的候选对象。在本报告中，我们在相关的啮齿类临床前模型中评估了一种针对AR LBD的DNA疫苗（pTVG - AR）的免疫和抗肿瘤功效。我们发现，用pTVG - AR对表达人类HLA - A2和HLA - DR1的HHDII - DR1小鼠进行免疫，可增强体内AR LBD的HLA - A2限制性肽特异性细胞毒性免疫反应，从而能够裂解人类前列腺癌细胞。利用一种表达HLA - A2的前列腺癌原位模型，用pTVG - AR免疫可增强HLA - A2限制性免疫反应，能够裂解同基因前列腺肿瘤细胞，并导致肿瘤负荷降低以及荷瘤动物的总体生存率提高。最后，免疫接种降低了哥本哈根大鼠的前列腺肿瘤生长，这与Th1型免疫反应有关。这些数据表明，AR是一种前列腺癌免疫靶抗原，并且一种针对AR LBD的DNA疫苗是一个有吸引力的临床评估候选对象。
The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. However, while it has long been the primary molecular target of metastatic prostate cancer therapies, it has not been explored as an immunotherapeutic target. In particular, the AR ligand-binding domain (LBD) is a potentially attractive target, as it has an identical sequence among humans as well as among multiple species, providing a logical candidate for preclinical evaluation. In this report, we evaluated the immune and anti-tumor efficacy of a DNA vaccine targeting the AR LBD (pTVG-AR) in relevant rodent preclinical models. We found immunization of HHDII-DR1 mice, which express human HLA-A2 and HLA-DR1, with pTVG-AR augmented AR LBD HLA-A2-restricted peptide-specific, cytotoxic immune responses in vivo that could lyse human prostate cancer cells. Using an HLA-A2-expressing autochthonous model of prostate cancer, immunization with pTVG-AR augmented HLA-A2-restricted immune responses that could lyse syngeneic prostate tumor cells and led to a decrease in tumor burden and an increase in overall survival of tumor-bearing animals. Finally, immunization decreased prostate tumor growth in Copenhagen rats that was associated with a Th1-type immune response. These data show that the AR is as a prostate cancer immunological target antigen and that a DNA vaccine targeting the AR LBD is an attractive candidate for clinical evaluation.
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