Mechanisms of Immune Suppression in Ovarian Cancer

卵巢癌的免疫抑制机制

• 批准号: 7727446
• 负责人: ELLEN L. GOODE
• 金额: $ 28万
• 依托单位: MAYO CLINIC ROCHESTER
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727446
• 关键词: Address; Alberta province; Animal Model; Animals; Antigen-Antibody Complex; Basic Science; Biological Models; Biological Response Modifiers; Biology; Biometry; Biostatistics Core; British Columbia; CD8B1 gene; Cancer Center; Cancer Patient; Cancer Prognosis; Cells; Cessation of life; Characteristics; Classification; Clinic; Clinical; Clinical Course of Disease; Clinical Data; Data; Dendritic Cells; Development; Elements; Environment; Extramural Activities; Freezing; Genes; Genetic; Goals; Grant; Gynecologic; Hawaii; Home environment; Human; Immune; Immune Targeting; Immune system; Immunity; Immunocompetent; Immunologic Surveillance; Immunologics; Immunosuppressive Agents; Immunotherapy; Inherited; Institutes; Instruction; Integration Host Factors; Interleukin-10; Letters; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Medical Research; Modeling; Multivariate Analysis; Mus; NCI Center for Cancer Research; Natural Immunity; Outcome; Ovarian; Pathogenesis; Patients; Phenotype; Population; Population Sciences; Prevention therapy; Queensland; Regulation; Regulator Genes; Reporting; Reproduction spores; Research Personnel; Role; Sampling; Single Nucleotide Polymorphism; Site; Staging; T cell regulation; T-Lymphocyte; Testing; The Sun; Universities; Variant; Washington; Woman; Work; base; cancer recurrence; chemotherapy; cooking; cytokine; improved; in vitro Model; malignant breast neoplasm; mortality; novel; novel therapeutics; ovarian cancer prevention; ovarian neoplasm; patient registry; programs; tumor

instaictions): Ovarian cancer has a high mortality rate and despite some improvements in survival with new chemotherapies, the cure rate has not improved in decades. While clinical features (e.g. stage) are excellent indicators of outcome, there remains significant variability in outcomes. Although recognized as an immune reactive malignancy, ovarian cancer eludes immunity due to a tumor-induced, complex immune suppressive network. In this project, we will examine determinants of immune suppression at an inherited level and at the level of the tumor microenvironment. We will then integrate inherited variation and novel tumor phenotypes with rich clinical annotation in biological models of these microenvironmental relationships and their impact on survival. We will study three unique elements of this network, specifically CD4+ T regulatory cells (Tregs), CD8+ Tregs, and PD-1 + expression on intratumoral dendritic cells (DC). Our general hypothesis is that immune suppression, which reflects a sophisticated interaction of a network of genes, molecules, and cells, contributes to ovarian cancer pathogenesis. This hypothesis is examined in the following aims. Specific Aim 1: To evaluate the association between inherited variation in 32 immune regulatory genes and overall survival among invasive ovarian cancer cases. Specific Aim 2: To determine the role of CD8+ Tregs and PD-1+ DC in the ovarian cancer immune microenvironment. Specific Aim 3: To assess the role of inherited variation in immune regulatory genes and intermediate tumor phenotypes in a multivariate model of survival in'ovarian cancer. Our proposed transdisciplinary project integrates population and basic research to increase our understanding of the immunologic mechanisms guiding relationships between host factors, immunologic tumor characteristics, and ovarian cancer outcome. Outcomes of this work will direct subsequent immune therapies in our already existing immunotherapy program. The clinically useful information developed in this grant will include the (1) identification of targets to block the suppressive mechanisms that ovarian cancers employ to evade immune surveillance and eradication, (2) identification of ways to better personalize use of novel immune-based therapies for the prevention of ovarian cancer recun'ence, and (3) identification of novel immune targets not currently addressed with immune-based therapies. Core Utilization Administrative, Biospecimens and Patient Registry, Biostatistics, and Animal Models Cores. Extramural Interactions Ovarian Cancer Association Consortium (OCAC), Dr. Mary L. Disis (University of Washington). Letters of Support Dr. Andrew Berchuck (Duke University), Dr. Georgia RELEVANCE (See Instructions): The proposed work will improve our understanding of the immune system and ovarian cancer pathogenesis. The results of this study will potentially be useful for ovarian cancer prognosis and the development of new therapeutic strategies.

Instaictions）： 卵巢癌的死亡率很高，尽管有新的生存情况有所改善 化学疗法，几十年来的治疗速率没有提高。而临床特征（例如阶段）很棒 结果的指标，结局的变化仍然很大。虽然被公认为免疫 反应性恶性肿瘤，由于肿瘤诱导的复杂免疫抑制作用，卵巢癌避免了免疫力 网络。在这个项目中，我们将检查在遗传水平和在 肿瘤微环境的水平。然后，我们将整合遗传变异和新型肿瘤 在这些微环境关系的生物学模型中，具有丰富临床注释的表型和 它们对生存的影响。我们将研究该网络的三个独特元素，特别是CD4+ T调节性 细胞（Tregs），CD8 + Tregs和PD-1 +表达在肿瘤内树突状细胞（DC）上。我们的将军 假设是免疫抑制，这反映了一个网络的复杂相互作用 基因，分子和细胞有助于卵巢癌发病机理。研究了这个假设 在以下目标中。特定目的1：评估32个免疫中遗传变异之间的关联 侵入性卵巢癌病例中的调节基因和总体生存。特定目标2：确定 CD8+ Treg和PD-1+ DC在卵巢癌免疫微环境中的作用。特定目标3： 评估遗传变异在免疫调节基因和中间肿瘤表型中的作用 诺瓦癌生存的多元模型。我们提议的跨学科项目整合了人口 和基础研究以增加我们对免疫机制指导关系的理解 在宿主因素，免疫肿瘤特征和卵巢癌结果之间。结果 工作将在我们已经存在的免疫疗法计划中指导后来的免疫疗法。临床上 本赠款中开发的有用信息将包括（1）标识目标以阻止抑制性 卵巢癌采用逃避免疫监视和消除的机制，（2）鉴定 更好地个性化新型免疫疗法来预防卵巢癌的方法 回收，（3）识别目前尚未使用免疫基于免疫的新型免疫靶标的 疗法。核心利用行政，生物测量和患者注册表，生物统计学和动物 型号。壁外相互作用卵巢癌协会联盟（OCAC），玛丽·L·迪斯（Mary L. Disis）博士 （华盛顿大学）。佐治亚博士的支持信安德鲁·伯查克（Andrew Berchuck）博士（杜克大学） 相关性（请参阅说明）： 拟议的工作将提高我们对免疫系统和卵巢癌发病机理的理解。 这项研究的结果可能对卵巢癌的预后和新的发展有用 治疗策略。