Adrenergic signaling inhibition to enhance the immunogenicity of the ovarian tumor microenvironment prior to PD-1 checkpoint therapy

项目主任/主要研究者（最后，第一，中间）：Armaiz-Pena，Guillermo N. 项目摘要 越来越多的证据表明，改变的心理状态，如慢性压力，焦虑和抑郁， 对卵巢癌患者有负面影响。多项研究报告称，卵巢癌患者患有 在诊断后和治疗期间心理痛苦增加，这导致 生活质量下降，总体生存率下降。这些改变的心理状态与增加的 应激激素水平、肿瘤相关炎症和疾病进展。支持这一提议的数据 展示了日常束缚应激如何导致细胞因子水平增加，巨噬细胞浸润和活性， 和卵巢癌的进展。另一方面，肾上腺素能信号如何影响抗- 肿瘤免疫应答仍然知之甚少。这一建议表明，卵巢癌腹水 癌症患者是高度免疫抑制的，从腹水中分离的T细胞表达大量的 抑制性标志物;使这项研究与最近针对卵巢癌T细胞的临床试验非常相关。 癌症没有成功。因此，总体假设表明，应激激素抑制抗肿瘤作用。 T细胞反应;因此，通过药理学方法阻断将增强T细胞功能并提高疗效 检查点抑制疗法在卵巢癌中的应用。特异性目的1将表征免疫学变化 肾上腺素能信号对卵巢癌患者细胞因子和T细胞反应的影响。在具体目标2中， 研究小组将通过以下临床前模型来确定日常束缚应激对T细胞功能的影响： 抗PD-1疗法和普萘洛尔治疗卵巢癌。研究小组相信，这一建议将 提供了一种全面的方法来剖析慢性应激对癌症相关免疫过程的作用， 例如T细胞功能和检查点抑制功效。结果从这个 一项提案将确定免疫反应的特征，并为旨在预防的干预措施提供理论依据。 治疗卵巢癌患者经历的慢性压力，最终目标是改善临床 对检查点阻断疗法的反应。 OMB编号0925-0001/0002（2018年1月批准至2020年3月31日修订版）页码续页格式页码

Program Director/Principal Investigator (Last, First, Middle): Armaiz-Pena, Guillermo N. PROJECT SUMMARY Growing evidence suggests that altered psychological states, such as chronic stress, anxiety, and depression negatively impact patients with ovarian cancer. Multiple studies report that ovarian cancer patients suffer from increased psychological distress following their diagnosis and during treatment, which contributes to worsened quality of life and decreased overall survival. These altered psychological states have been linked to increased stress hormones levels, tumor-associated inflammation, and disease progression. Data supporting this proposal demonstrates how daily restraint stress leads to increased cytokine levels, macrophage infiltration and activity, and ovarian cancer progression in animal models. On the other hand, how adrenergic signaling affects anti- tumor immune responses remains poorly understood. This proposal demonstrates that ascites from ovarian cancer patients are highly immunosuppressed and T-cells isolated from ascites express an abundance of inhibitory markers; making this research extremely relevant as recent clinical trials targeting T cells in ovarian cancer have not been successful. Hence, the overall hypothesis states that stress hormones suppress anti-tumor T cell responses; thus, blockade by pharmacologic methods will enhance T cell function and improve the efficacy of checkpoint inhibition therapy in ovarian cancer. Specific Aim 1 will characterize the immunologic changes that adrenergic signaling has on cytokines and T cell responses in ovarian cancer patients. In Specific Aim 2, the study team will determine the impact of daily restraint stress on T cell function through pre-clinical models of ovarian cancer treated with anti-PD-1 therapy and propranolol. The study team is confident that this proposal will provide a comprehensive approach to dissect the role of chronic stress on cancer-associated immune processes, such as T cell function and checkpoint inhibition efficacy, that lead to disease progression. Results from this proposal will identify immune signatures of response and provide a rationale for interventions aimed at preventing and treating chronic stress experienced by ovarian cancer patients, with the ultimate goal of improving clinical responses to checkpoint blockade therapy. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page