Mechanisms of Immune Suppression in Ovarian Cancer

instaictions）： 卵巢癌的死亡率很高，尽管新疗法的生存率有所提高， 化疗，治愈率几十年来没有提高。虽然临床特征（如分期）很好， 尽管成果指标的差异很大，但成果仍存在很大差异。虽然被公认为免疫 反应性恶性肿瘤，卵巢癌逃避免疫，由于肿瘤诱导的，复杂的免疫抑制 网络在这个项目中，我们将研究免疫抑制的决定因素在遗传水平和 肿瘤微环境的水平。然后我们将整合遗传变异和新肿瘤 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， 对生存的影响。我们将研究这个网络的三个独特元素，特别是CD 4 + T调节 细胞（TcB）、CD 8 + TcB和肿瘤内树突状细胞（DC）上的PD-1 +表达。我们的一般 一种假说是，免疫抑制，反映了一个复杂的相互作用的网络， 基因、分子和细胞，有助于卵巢癌的发病机制。这一假设是检验 在以下目标中。具体目的1：评估32个免疫缺陷型中遗传变异之间的相关性， 浸润性卵巢癌病例中的调节基因和总生存率。具体目标2：确定 CD 8 + T淋巴细胞和PD-1+ DC在卵巢癌免疫微环境中的作用。具体目标3： 评估免疫调节基因和中间肿瘤表型的遗传变异在肿瘤发生中的作用。 卵巢癌生存率的多变量模型。我们提出的跨学科项目将人口 和基础研究，以增加我们对免疫机制的理解， 宿主因素、免疫肿瘤特征和卵巢癌预后之间的关系。这件事的结果 这项工作将指导我们现有免疫治疗计划中的后续免疫治疗。述临床 在这项赠款中开发的有用信息将包括：（1）识别目标，以阻止抑制 卵巢癌逃避免疫监视和根除的机制，（2）识别 如何更好地个性化使用新的基于免疫的疗法来预防卵巢癌 recun'ence，和（3）识别目前没有解决的新的免疫靶点与免疫为基础的 治疗核心利用管理、生物标本和患者登记、生物统计和动物 模型核心。体外相互作用卵巢癌协会联盟（OCAC），博士玛丽L。迪西斯 （华盛顿大学）。支持信Andrew Berchuck博士（杜克大学），格鲁吉亚博士 相关性（见说明）： 这项工作将提高我们对免疫系统和卵巢癌发病机制的理解。 这项研究的结果将可能有助于卵巢癌的预后和新的治疗方法的开发。 治疗策略

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.