Regulatory T Cell Function in Ovarian Cancer

描述（由申请人提供）：尽管新出现的证据表明与免疫反应相关的因素在卵巢癌的发展和临床治疗中起着重要作用，但卵巢癌的病因和预后因素仍然知之甚少。最近的证据表明，具有免疫抑制特性的T细胞亚群，被称为调节性T细胞（Treg），对自身耐受性的发展和维持至关重要。有非常一致的文献指出这些Treg细胞在人类健康中的重要作用。这些研究表明，较低的外周Treg细胞表达与自身免疫性疾病、过敏和不良移植结果相关，表明Treg细胞刺激的免疫抑制不足可能导致这些自身反应性健康状况的发展。另一方面，在多种恶性肿瘤患者中不断报道Treg细胞表达升高，这表明Treg细胞介导的抑制可能会干扰对肿瘤相关抗原的充分免疫反应。我们的研究小组和其他研究小组也提供了直接证据，表明Treg细胞表达升高与卵巢癌风险增加和预后较差有关。因此，Treg细胞在癌症病因学和预后中的作用是一个新兴的兴趣领域，因为高Treg活性可能a)在癌症发生和进展时阻止适当的免疫反应，b)在肿瘤初始治疗后阻止适当的免疫反应；c)导致对肿瘤免疫治疗的反应性降低。到目前为止，我们还不知道有任何全面的流行病学研究集中在Treg细胞在人类癌症中的作用，特别是卵巢癌的发生。因此，我们建议评估Treg细胞负荷以及一组与Treg细胞活性直接相关的候选遗传多态性在卵巢癌病因学和预后中的作用。我们在Aim 1中假设患有卵巢癌的女性血液中Treg细胞水平高于健康对照组。我们也期望在Aim 2中，具有基因决定的高活性Treg细胞谱的女性在卵巢癌发生的起始和进展阶段对肿瘤细胞进行免疫应答的效果较差。我们在Aim 3中进一步假设，具有遗传决定的高活性Treg细胞谱的卵巢癌患者在对抗残留疾病时效果较差。我们还试图在Aim 4中确定Treg细胞功能的遗传变异是否可以预测Treg细胞在卵巢肿瘤中的表达。我们建议利用我们研究所的核心资源和基于人群的卵巢癌病例对照研究的数据和标本。在Aim 1中，我们将通过我们研究所的生物库新招募100名卵巢癌患者和100名对照组，收集Treg细胞测量所需的新鲜血液样本。在病例对照研究中，我们最近从纽约州布法罗、宾夕法尼亚州匹兹堡和俄亥俄州克利夫兰地区招募了900多名卵巢癌患者和1800名社区对照（Specific Aim 2）。我们建议对卵巢癌患者组进行随访，并评估相关的临床结果（复发、生存；Specific Aim 3）。我们还将从我们研究所的卵巢癌标本银行（Specific Aim 4）中选择630名具有可用血液和肿瘤样本的晚期疾病患者。对于实验室分析，我们将分别使用Illumina Golden Gate检测和流式细胞术技术进行基因型和Treg细胞评估。我们的统计和遗传分析将由训练有素的遗传流行病学家进行。公共卫生相关性：这项拟议的研究将是对调节性T细胞在卵巢癌发生中的作用的首次全面调查。这项研究的结果将有助于我们了解卵巢癌的发生和发展过程。这项研究的发现也可以为这种严重疾病的新型免疫治疗策略奠定基础，并可以确定可能从这些新疗法中获益最多的妇女亚组。

DESCRIPTION (provided by applicant): Etiologic and prognostic factors in ovarian cancer remain poorly understood, although emerging evidence suggests that factors related to immune response play important roles in the development and clinical treatment of this disease. Recent evidence has revealed that a subset of T cells with immunosuppressive properties, referred to as regulatory T cells (Treg), are essential for the development and maintenance of self-tolerance. There is a very consistent body of literature that points to an important role of these Treg cells in human health. These studies have shown that lower peripheral Treg cells expression is associated with autoimmune disease, allergy, and adverse transplantation outcomes, indicating that insufficient Treg cell stimulated immune suppression might lead to the development of these auto reactive health conditions. On the other hand, elevated Treg cell expression has been consistently reported in patients with a wide variety of malignancies, suggesting that Treg cell-mediated suppression might interfere with an adequate immune response to tumor associated antigens. Our group and others also provided direct evidence linking elevated Treg cell expression to greater risk of ovarian cancer and poorer prognosis. Thus, the role of Treg cells in cancer etiology and prognosis is an area of emerging interest, as high Treg activity might a) prevent an adequate immune response at the time of cancer initiation and progression, b) prevent an adequate immune response after initial treatment of the tumor; and c) result in lower responsiveness to tumor immunotherapy. To date, we are unaware of any comprehensive epidemiological study that has focused on the role Treg cells in human cancer in general or ovarian carcinogenesis in particular. Thus, we propose to evaluate the role of Treg cell burden as well as a panel of candidate genetic polymorphisms, directly relevant to Treg cell activity, in the etiology and prognosis of ovarian cancer. We hypothesize in Aim 1 that women with ovarian cancer will have higher blood Treg cell levels than healthy controls. We also expect in Aim 2 that women with a genetically determined high activity Treg cell profile will be less effective in mounting an immune response toward tumor cells in the initiation and progression phase of ovarian carcinogenesis. We further hypothesize in Aim 3 that ovarian cancer patients with a genetically determined high activity Treg cell profile will be less effective in battling residual disease. We also seek to determine in Aim 4 if genetic variability in Treg cell function can predict Treg cell expression in ovarian tumors. We propose to utilize data and specimens from core resources at our institute and from a population-based case-control study of ovarian cancer. For Aim 1, we will newly recruit 100 ovarian cancer patients and 100 controls via our institute's Biorepository to collect fresh blood samples required for Treg cell measurements. In the case-control study we recently recruited over 900 ovarian cancer patients and 1800 community controls (Specific Aim 2) from the Buffalo, NY, Pittsburgh PA, and Cleveland, OH areas. We propose to follow-up the ovarian cancer patient group and assess relevant clinical outcomes (recurrence, survival; Specific Aim 3). We will also select 630 patients with advanced stage disease with available blood and tumor samples from our institute's Ovarian Cancer Specimen Bank (Specific Aim 4). For the laboratory analyses, we will utilize Illumina Golden Gate assays and flow-cytometry techniques for the genotype and Treg cell assessment, respectively. Our statistical and genetic analyses will be carried out by a trained geneti epidemiologist. PUBLIC HEALTH RELEVANCE: The proposed study will be the first comprehensive investigation on the role of regulatory T cells in ovarian carcinogenesis. Results from this research will contribute to our understanding on how ovarian cancer develops and progresses. Findings from this study can also lay the foundation for novel immunotherapeutic strategies for this serious disease and can identify subgroups of women who might benefit most from these new therapies.