Mechanisms of Immune Suppression in Ovarian Cancer

安装)： 卵巢癌死亡率很高，尽管新的治疗方法在生存率方面有所改善 化疗，治愈率几十年来没有提高。虽然临床特征(如分期)很好 在成果指标方面，成果仍然具有很大的变异性。尽管被认为是一种免疫 反应性恶性肿瘤，卵巢癌由于肿瘤诱导的复杂免疫抑制而逃避免疫 网络。在这个项目中，我们将在遗传水平和水平上检查免疫抑制的决定因素 肿瘤微环境的水平。然后我们将整合遗传变异和新的肿瘤 在这些微环境关系的生物学模型中具有丰富的临床注释的表型和 它们对生存的影响。我们将研究这个网络的三个独特元素，特别是CD4T调节 瘤内树突状细胞(DC)表达CD8Tregs、CD8Tregs和PD-1。我们的将军 假设是免疫抑制，这反映了一个复杂的相互作用的网络 基因、分子和细胞参与了卵巢癌的发病机制。这一假设得到了检验。 在以下目标中。具体目标1：评估32例免疫疾病的遗传变异之间的关系 卵巢癌侵袭性病例中的调控基因和总体生存率。具体目标2：确定 CD8Tregs和PD-1 DC在卵巢癌免疫微环境中的作用具体目标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 卵巢癌患者生存的多因素模型.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指导关系的理解 宿主因素、免疫学肿瘤特征和卵巢癌预后之间的关系。这样做的结果是 这项工作将指导我们已经存在的免疫治疗计划中的后续免疫治疗。临床上的 在这笔赠款中开发的有用信息将包括：(1)识别目标以阻止压制 卵巢癌逃避免疫监视和根除的机制，(2)鉴定 如何更好地个人化使用基于免疫的新疗法来预防卵巢癌 复发，以及(3)识别目前尚未用基于免疫的方法解决的新的免疫靶点 治疗。核心利用管理、生物检疫和患者登记、生物统计学和动物 模型核心。卵巢癌协会联合会(OCAC)，玛丽·L·迪西斯博士 (华盛顿大学)。支持信：安德鲁·伯查克博士(杜克大学)，乔治亚博士 相关性(请参阅说明)： 这项拟议的工作将提高我们对免疫系统和卵巢癌发病机制的理解。 本研究的结果将对卵巢癌的预后和新的卵巢癌的发展具有潜在的参考价值。 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.