B7-H1 Signaling in Ovarian Cancer

描述（由申请人提供）：项目概述。我们已经证明调节性T细胞（Tregs）可以击败抗癌免疫，它们的消耗可以起到治疗作用，但它们的快速再生是有问题的。该项目利用我们的发现，B7-H1免疫共信号促进Treg的产生和雌激素受体（ER）？在相关的临床前小鼠模型中，信号抑制Treg再生，证明具有实质性的翻译相关性。最初的研究集中在卵巢癌（OC）上，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各样的癌症。B7-H1对ER的影响信号和免疫病理和临床结果的关系进行了研究。我们的首要目标是确定新的和有效的癌症免疫疗法，重点是卵巢癌。我们的首要假设是B7-H1阻断将增加Treg消耗作为癌症免疫治疗和ER？信号会增强B7-H1的阻断作用。这一假设预测了卵巢癌免疫治疗的新方法，极大地扩展了我们对其免疫发病机制的理解，并允许开发用于其他癌症和男性的类似策略。呃?激动剂可以用于男性，正如我们所展示的，并避免雌激素的副作用。

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.