Regulatory T Cell Function in Ovarian Cancer

描述(申请人提供)：卵巢癌的病因和预后因素仍然知之甚少，尽管新出现的证据表明，与免疫反应有关的因素在这种疾病的发展和临床治疗中发挥着重要作用。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)，对于自我耐受的发展和维持是必不可少的。有非常一致的文献指出这些Treg细胞在人类健康中扮演着重要的角色。这些研究表明，外周血Treg细胞表达降低与自身免疫性疾病、过敏和不良移植结果有关，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生。另一方面，在多种恶性肿瘤患者中，Treg细胞表达的升高一直被报道，这表明Treg细胞介导的抑制可能干扰了对肿瘤相关抗原的足够免疫反应。我们的小组和其他人也提供了直接证据，表明Treg细胞表达增加与卵巢癌的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出现的感兴趣的领域，因为高Treg活性可能a)在癌症发生和发展时阻止足够的免疫反应，b)阻止肿瘤最初治疗后的充分免疫反应，以及c)导致对肿瘤免疫治疗的低反应性。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细胞在一般人类癌症或特别是卵巢癌发生中的作用。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基因多态在卵巢癌的病因和预后中的作用。我们在目标1中假设，卵巢癌患者的血液Treg细胞水平将高于健康对照组。我们还预计，在AIM 2中，具有基因决定的高活性Treg细胞图谱的女性在卵巢癌发生的起始和进展阶段对肿瘤细胞的免疫反应将不那么有效。我们在AIM 3中进一步假设，具有基因决定的高活性Treg细胞图谱的卵巢癌患者在对抗残留疾病方面将不太有效。我们还试图在AIM 4中确定Treg细胞功能的遗传变异性是否可以预测卵巢肿瘤中Treg细胞的表达。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样本。对于目标1，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，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(特定目标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、生存率；特定目标3)。我们还将从我所卵巢癌标本库(特定目标4)中选择630例有可用的血液和肿瘤标本的晚期疾病患者。对于实验室分析，我们将分别使用Illumina Golden Gate分析和流式细胞仪技术进行基因分型和Treg细胞评估。我们的统计和遗传分析将由一名训练有素的Geneti流行病学家进行。公共卫生相关性：这项拟议的研究将是关于调节性T细胞在卵巢癌发生中的作用的第一次全面调查。这项研究的结果将有助于我们理解卵巢癌的发生和发展。这项研究的发现还可以为这种严重疾病的新免疫治疗策略奠定基础，并可以确定可能从这些新疗法中受益最大的妇女亚群。

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.