In vivo effects of vaccination with six-transmembrane epithelial antigen of the prostate:: A candidate antigen for treating prostate cancer
In vivo effects of vaccination with six-transmembrane epithelial antigen of the prostate:: A candidate antigen for treating prostate cancer
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DOI：
10.1158/0008-5472.can-06-2996
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Kast, W. Martin
中科院分区：
文献类型：
--
作者：
Garcia-Hernandez, Maria de la Luz;Gray, Andrew;Kast, W. Martin
免疫疗法可能为癌症患者提供另一种治疗方法，特别是当肿瘤过度表达可被免疫细胞识别的抗原时。前列腺癌中上调的标志物和治疗靶点的鉴定对于设计新的前列腺癌潜在治疗方法非常重要。其中，最近发现的前列腺六跨膜上皮抗原（STEAD）由于其在人类前列腺癌组织中过度表达而被认为具有吸引力。我们的研究首次评估了基于 STEAD 的疫苗接种在预防性和治疗性小鼠模型中的体内有效性。使用两种递送系统，即基因枪递送的 cDNA 和委内瑞拉马脑炎病毒样复制子颗粒 (VRP)，均编码小鼠 STEAD (mSTEAp) 和三种疫苗接种策略。我们的结果表明，基于 mSTEAP 的疫苗接种能够诱导针对新定义的 mSTEAP 表位的特异性 CD8 T 细胞反应，从而非常显着地延长肿瘤攻击小鼠的总体存活率。这是在没有任何自身免疫发展的情况下实现的。令人惊讶的是，在我们的模型中，CD4 T 细胞产生 IFN γ、肿瘤坏死因子-α (TNF-α) 和白细胞介素-2 (IL-2)，在肿瘤排斥中发挥了主要作用，如使用 CD4 和 CD8 缺陷小鼠所显示的。此外，肿瘤环境中高水平 IL-12 的存在与良好的抗肿瘤反应相关。最后，还评估了 STEAD 疫苗接种的治疗效果，并诱导了 31 天龄肿瘤的生长适度但显着的延迟。综上所述，我们的数据表明，针对 mSTEAP 的疫苗接种是延缓肿瘤生长的可行选择。
Immunotherapy may provide an alternative treatment for cancer patients, especially when tumors overexpress antigens that can be recognized by immune cells. The identification of markers and therapeutic targets that are up-regulated in prostate cancer has been important to design new potential treatments for prostate cancer. Among them, the recently identified six-transmembrane epithelial antigen of the prostate (STEAD) is considered attractive due to its overexpression in human prostate cancer tissues. Our study constitutes the first assessment of the in vivo effectiveness of STEAD-based vaccination in prophylactic and therapeutic mouse models. Two delivery systems, cDNA delivered by gene gun and Venezuelan equine encephalitis virus-like replicon particles (VRP), both encoding mouse STEAD (mSTEAp) and three vaccination strategies were used. Our results show that mSTEAP-based vaccination was able to induce a specific CD8 T-cell response against a newly defined mSTEAP epitope that prolonged the overall survival rate in tumor-challenged mice very significantly. This was achieved without any development of autoimmunity. Surprisingly, CD4 T cells that produced IFN gamma, tumor necrosis factor-alpha (TNF-alpha), and interleukin-2 (IL-2) played the main role in tumor rejection in our model as shown by using CD4- and CD8-deficient mice. In addition, the presence of high IL-12 levels in the tumor environment was associated with a favorable antitumor response. Finally, the therapeutic effect of STEAD vaccination was also assessed and induced a modest but significant delay in growth of established, 31 day old tumors. Taken together, our data suggest that vaccination against mSTEAP is a viable option to delay tumor growth.