Regulatory T Cell Function in Ovarian Cancer

卵巢癌中的调节性 T 细胞功能

• 批准号: 8268490
• 负责人: KIRSTEN B. MOYSICH
• 金额: $ 58.71万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268490
• 关键词: Alleles; Area; Autoimmune Diseases; Biological Assay; Blood; Blood specimen; Buffaloes; Cancer Etiology; Cancer Patient; Cancer Prognosis; Case-Control Studies; Cell physiology; Cells; Characteristics; Clinical; Clinical Treatment; Communities; Data; Development; Diagnostic Neoplasm Staging; Disease; Disease-Free Survival; Epidemiologic Studies; Epidemiologist; Epidemiology; Etiology; Favorable Clinical Outcome; Flow Cytometry; Foundations; Frequencies; Genes; Genetic; Genetic Polymorphism; Genotype; Health; Human; Hypersensitivity; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Institutes; Interleukin-2; Investigation; Laboratories; Lead; Link; Literature; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Measurement; Mediating; Methodology; Oncogenes; Operative Surgical Procedures; Outcome; Outcome Measure; Ovarian; Patients; Peripheral; Phase; Pilot Projects; Play; Prognostic Factor; Property; Recruitment Activity; Recurrence; Recurrent disease; Regulatory T-Lymphocyte; Reporting; Research; Residual Tumors; Resources; Risk; Role; Sampling; Self Tolerance; Single Nucleotide Polymorphism; Specimen; Staging; Subgroup; T-Lymphocyte Subsets; Techniques; Testing; Time; Training; Transplantation; Tumor Antigens; Woman; abstracting; advanced disease; biobank; cancer initiation; carcinogenesis; clinically relevant; clinically significant; effective therapy; follow-up; genetic analysis; interest; neoplastic cell; novel; outcome forecast; ovarian neoplasm; peripheral blood; population based; prevent; tumor; tumor progression

Abstract 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 genetic epidemiologist.

摘要 卵巢癌的病因学和预后因素仍然知之甚少， 有证据表明，与免疫反应相关的因素在免疫系统中起着重要作用。 发展和临床治疗。最近的证据显示， 具有免疫抑制特性的T细胞，称为调节性T细胞（Treg）， 这对发展和维持自我耐受性至关重要。有一个非常一致的 这些文献指出了这些Treg细胞在人类健康中的重要作用。这些 研究表明，外周Treg细胞表达降低与自身免疫相关， 疾病，过敏和不良移植结果，表明Treg细胞不足， 刺激免疫抑制可能导致这些自身反应性健康的发展 条件另一方面，Treg细胞表达的升高一直被报道， 患者的各种恶性肿瘤，表明Treg细胞介导的抑制， 可能干扰对肿瘤相关抗原的充分免疫应答。我们集团 其他人也提供了直接证据，将Treg细胞表达升高与更大的风险联系起来。 卵巢癌预后差。因此，Treg细胞在癌症病因学中的作用和 预后是一个新兴的兴趣领域，因为高Treg活性可能a）阻止足够的免疫应答， B）在癌症开始和发展时阻止足够的免疫应答， 肿瘤初始治疗后的免疫应答;和c）导致对以下的较低应答： 肿瘤免疫治疗到目前为止，我们还没有任何全面的流行病学研究， 该研究主要关注Treg细胞在人类癌症中的作用， 特别的。因此，我们建议评估Treg细胞负荷的作用以及一组 与Treg细胞活性直接相关的候选遗传多态性，在病因学和 卵巢癌的治疗我们在目标1中假设，患有卵巢癌的女性 血液Treg细胞水平高于健康对照组。我们还希望在目标2中， 基因决定的高活性Treg细胞谱在安装免疫系统中将不太有效。 卵巢癌发生的起始和进展阶段对肿瘤细胞的反应。 我们在目标3中进一步假设，具有遗传决定性高表达的卵巢癌患者， 活性Treg细胞谱在对抗残留疾病中的有效性将降低。我们还寻求 在目的4中确定Treg细胞功能的遗传变异性是否可以预测Treg细胞表达， 卵巢肿瘤我们建议利用我们研究所核心资源中的数据和标本 和基于人群的卵巢癌病例对照研究。对于目标1，我们将新 通过我们研究所的生物储存库招募100名卵巢癌患者和100名对照， Treg细胞测量所需的新鲜血液样本。在最近的病例对照研究中， 招募了900多名卵巢癌患者和1800名社区对照（特定目标2）， 纽约州的布法罗、宾夕法尼亚州的匹兹堡和俄亥俄州的克利夫兰地区。我们建议对卵巢进行随访 癌症患者组，并评估相关的临床结果（复发，生存;具体目标 3）。我们还将选择630例具有可用血液和肿瘤的晚期疾病患者 来自我们研究所卵巢癌标本库的样本（特定目标4）。为实验室 分析，我们将利用Illumina Golden Gate检测和流式细胞术技术， 基因型和Treg细胞评估。我们的统计学和遗传学分析 由训练有素的遗传流行病学家进行。