B7-H1 Signaling in Ovarian Cancer

描述(申请人提供)：项目摘要。我们已经证明，调节性T细胞(Treg)击败了抗癌免疫，它们的耗尽可以起到治疗作用，但它们的快速再生是有问题的。这个项目利用了我们的发现，即B7-H1免疫共信号促进Treg的产生，以及雌激素受体(ER？在相关的临床前小鼠模型中，信号抑制Treg再生，这与已证实的实质性翻译相关性有关。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癌症。B7-H1对ER？信号及其与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OC。我们的主要假设是，阻断B7-H1将增加Treg作为癌症免疫治疗的耗竭，而ER？信号将增强B7-H1的封锁效果。这一假说预测了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，并允许为其他癌症和男性开发类似的策略。呃？正如我们已经证明的，激动剂可以用于男性，并避免雌激素的副作用。 具体目标是：目标1检验ER？信号增强B7-H1在癌症中的阻断作用，目的2验证癌症中功能失调的B7-H1信号是树突状细胞依赖的假设。这些目的是通过使用信号成分基因为零的小鼠、影响关键信号通路的药物和骨髓嵌合体来研究造血和非造血B7-H1信号来实现的。 关联性。我们寻求改善OC的治疗选择，这种疾病每年导致超过15,000名美国妇女死亡，一线治疗失败后没有治愈的选择，就像大多数情况下所做的那样。原理可以应用于多种癌症，包括黑色素瘤，在这里作为第二种确诊癌症进行研究。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，到目前为止，该疗法的成功记录还不算多。 公共卫生相关性：该项目确定了利用调节性T细胞耗竭和雌激素受体-？来改善抗B7-H1抗体免疫共信号阻断的临床和免疫有效性的方法。卵巢癌(ID8肿瘤)和黑色素瘤(B16肿瘤)临床前模型中的激动剂。B7-H1信号在卵巢癌和黑色素瘤中的免疫病理基础也将被定义。

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. PUBLIC HEALTH RELEVANCE: This project identifies means to improve the clinical and immune effectiveness of immune co-signaling blockade with anti-B7-H1 antibodies, using regulatory T cell depletion and estrogen receptor-? agonists in preclinical models for ovarian cancer (ID8 tumor) and melanoma (B16 tumor). The immunopathologic basis of B7-H1 signals in ovarian cancer and melanoma will be defined as well.