A Transgenic Model for Prostate Tumor Immunity

描述（由申请人提供）：前列腺癌是美国男性中最常见的恶性肿瘤，每年导致超过30，000人死亡。这种高死亡率主要是由于标准疗法无法有效治疗疾病的转移形式。基于免疫的疗法代表了治疗前列腺癌的一种有前途的新方法，部分原因是针对非恶性组织的自身免疫的可能发展（大多数基于免疫的疗法的潜在副作用）不会有问题，因为前列腺是非必需器官。几个参数可以影响基于T细胞的疗法治疗癌症的功效，其中最关键的参数之一是对靶向肿瘤抗原的耐受性的发展。为了研究前列腺癌和T细胞耐受性之间的关系，我们开发了一种新的转基因小鼠系统，在该系统中，我们可以在各种环境中检查对前列腺上皮抗原特异性的CD4细胞克隆型群体的功能状态：1）在没有疾病的情况下，2）在前列腺癌的发展期间，和3）在雄激素消融（前列腺癌的标准治疗）之后。我们的初步数据表明，虽然前列腺上皮特异性CD4细胞通常不知道它们的同源抗原，但晚期前列腺癌的发展将这种被动形式的耐受性转化为更主动的耐受性，其中这些T细胞在功能上无应答。有趣的是，雄激素消融减轻了前列腺肿瘤的致耐受性潜力，可能是通过降低致耐受性抗原呈递的总体水平，并可能产生一个治疗窗口，在此期间耐受性可能对肿瘤免疫性的阻碍较小。在这个提议中，我们将通过确定耐受性发展的疾病阶段以及诱导耐受性的机制来更详细地研究前列腺肿瘤发生和T细胞耐受性之间的关系。此外，我们将把这些知识应用于疫苗策略的设计，以在各种治疗环境中治疗前列腺癌（包括雄激素消融术后）。

DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed malignancy in American men, resulting in over 30,000 deaths annually. This high rate of mortality results mainly from the inability of standard therapies to effectively treat the metastatic form of the disease. Immune-based therapies represent a promising new approach to treating prostate cancer in part because the possible development of autoimmunity against non-malignant tissue (a potential side effect for most immune-based therapies) would not be problematic because the prostate is a non-essential organ. Several parameters can influence the efficacy of T cell-based therapies to treat cancer, one of the most critical being the development of tolerance towards the targeted tumor-antigens. To study the relationship between prostate cancer and T cell tolerance, we have developed a novel transgenic mouse system in which we can examine the functional status of a clonotypic population of CD4 cells specific for a prostate epithelial antigen in a variety of settings: 1) in the absence of disease, 2) during the development of prostate cancer, and 3) following androgen-ablation (a standard treatment for prostate cancer). Our preliminary data indicates that while prostate epithelial-specific CD4 cells are normally ignorant of their cognate antigen, the development of advanced prostate cancer converts this passive form of tolerance into a more active one in which these T cells are rendered functionally non-responsive. Interestingly, androgen-ablation mitigates the tolerogenic potential of prostate tumors, presumably by reducing the overall levels of tolerogenic antigen presentation, and potentially creating a therapeutic window during which tolerance might be less of an impediment towards tumor immunity. In this proposal we will investigate in more detail the relationship between prostate tumorigenesis and T cell tolerance by determining the disease stage at which tolerance develops, as well as the mechanisms by which tolerance is induced. Furthermore, we will apply this knowledge to the design of vaccine strategies to treat prostate cancer in a variety of therapeutic settings (including following androgen-ablation).