B7-H1 Signaling in Ovarian Cancer

描述（由申请人提供）：项目摘要。我们已经表明，调节性T细胞（Tcells）击败抗癌免疫，并且它们的消耗可以是治疗性的，但它们的快速再生是有问题的。该项目使用我们的发现，B7-H1免疫共信号促进Treg生成和雌激素受体（ER）？信号在相关临床前小鼠模型中抑制Treg再生，具有已证实的实质性翻译相关性。最初的研究集中在卵巢癌（OC），并使用黑色素瘤模型来证明其他肿瘤的概念，因为我们的发现应该适用于各种癌症。B7-H1对ER？研究了信号传导以及与免疫病理学和临床结果的关系。我们的首要目标是确定新的和有效的癌症免疫疗法，重点是OC。我们的总体假设是，B7-H1阻断将增加Treg耗竭作为癌症免疫疗法，ER？信号将增强B7-H1阻断效应。这一假设预测了OC免疫治疗的新方法，极大地扩展了我们对其免疫发病机制的理解，并允许针对其他癌症和男性开发类似的策略。急诊室？如我们所示，激动剂可用于男性，并避免雌激素副作用。 具体目标是目标1测试的假设，ER？信号增强了B7-H1在癌症和AIM中的阻断作用2测试癌症中功能失调的B7-H1信号传导依赖于树突状细胞的假设。这些目标是使用遗传上无信号成分的小鼠、影响关键信号通路的药物和骨髓嵌合体来研究造血与非造血B7-H1信号来实现的。 本案无关我们寻求改善OC的治疗选择，OC每年导致超过15，000名美国妇女死亡，并且在一线治疗失败后没有治愈选择，因为它在大多数情况下都是如此。这些原则可以应用于各种各样的癌症，包括黑色素瘤，在这里作为一种确认性的第二种癌症进行研究。我们对肿瘤相关免疫功能障碍的见解有望帮助提高癌症免疫疗法的疗效，迄今为止，癌症免疫疗法的成功记录并不多。

DESCRIPTION (provided by applicant): Project Summary. We have shown that regulatory T cells (Tregs) defeat anti-cancer immunity and that their depletion can be therapeutic, but their rapid regeneration is problematic. This project uses our discoveries that B7-H1 immune co-signaling facilitates Treg generation and that estrogen receptor (ER)? signals inhibit Treg regeneration in relevant pre-clinical mouse models with proven substantial translational relevance. Initial studies focus on ovarian cancer (OC) and use melanoma models to demonstrate concepts in additional tumors, as our discoveries should be applicable to a wide variety of cancers. Effects of B7-H1 on ER? signaling and relations to immune pathology and clinical outcomes are studied. Our overarching objective is to identify novel and effective immune therapy for cancers, with a focus on OC. Our overarching hypothesis is that B7-H1 blockade will augment Treg depletion as cancer immunotherapy and that ER? signals will boost B7-H1 blockade effects. This hypothesis predicts novel approaches to immunotherapy for OC, greatly extends our understanding of its immunopathogenesis and allows development of a similar strategy for other cancers and in men. ER? agonists can be used in males as we have shown and avoid estrogen side effects. The specific aims are Aim 1 Test the hypothesis that ER? signals augment B7-H1 blockade effects in cancer and AIM 2 Test the hypothesis that dysfunctional B7-H1 signaling in cancer is dendritic cell-dependent. These aims are achieved using mice genetically null for signaling components, pharmacologic agents affecting key signaling pathways, and bone marrow chimeras to study hematopoietic versus non-hematopoietic B7-H1 signals. Relevance. We seek to improve treatment options for OC, which kills over 15,000 American women annually, and for which there is no curative option after first-line therapy fails, as it doe in most cases. Principles can be applied to a wide variety of cancers, including melanoma, studied here as a confirmatory second cancer. Our insights into tumor-associated immune dysfunction promise to help improve the efficacy of cancer immunotherapy, whose record of success to date has been only modest.