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

在 PD-1 检查点治疗之前抑制肾上腺素信号传导以增强卵巢肿瘤微环境的免疫原性

• 批准号: 10056699
• 负责人: GUILLERMO N ARMAIZ-PENA
• 金额: $ 43.81万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-03 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056699
• 关键词: Academic Medical Centers; Adjuvant; Adrenergic Agents; Affect; Animal Model; Anxiety; Area; Ascites; Blood; CD8-Positive T-Lymphocytes; CXCL5 gene; Cancer Center; Cancer Patient; Cell physiology; Cells; Chronic stress; Clinical; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Cryopreservation; Data; Diagnosis; Disease Progression; Environment; Future; Generations; Goals; Hormones; Hypothalamic structure; Immune; Immune checkpoint inhibitor; Immune response; Immunologics; Immunotherapy; Impairment; Infiltration; Inflammation; Inflammatory; Infrastructure; Intervention; Lead; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mental Depression; Methods; Outcome; PD-1 blockade; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Pilot Projects; Pituitary-Adrenal System; Platelet-Derived Growth Factor; Pre-Clinical Model; Principal Investigator; Process; Production; Propranolol; Quality of life; Reporting; Research; Research Institute; Research Personnel; Resources; Role; Serum; Signal Pathway; Signal Transduction; Stress; Sympathetic Nervous System; System; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Tumor-Infiltrating Lymphocytes; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; base; biobank; cancer cell; cancer health disparity; cancer therapy; checkpoint inhibition; checkpoint therapy; cytokine; efficacy testing; exhaust; exhaustion; experience; experimental study; immune checkpoint blockade; immunogenicity; immunosuppressed; improved; interest; macrophage; melanoma; member; mouse model; ovarian neoplasm; pre-clinical; prevent; programmed cell death protein 1; programs; psychologic; psychological distress; receptor; response; restraint stress; standard of care; stress state; tumor; tumor microenvironment; tumor progression

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

项目总监/首席研究员（最后，第一，中间）：Armaiz-Pena，Guillermo N. 项目摘要 越来越多的证据表明，心理状态改变了，例如慢性压力，焦虑和抑郁 负面影响卵巢癌患者。多项研究报告说，卵巢癌患者患有 诊断后和治疗期间的心理困扰增加，这导致恶化 生活质量和总体生存下降。这些改变的心理状态与增加有关 应力激素水平，肿瘤相关炎症和疾病进展。支持该建议的数据 证明每日约束应力如何导致细胞因子水平升高，巨噬细胞浸润和活性， 动物模型中的卵巢癌进展。另一方面，肾上腺素信号如何影响抗 肿瘤免疫反应仍然很少了解。该提议表明卵巢的腹水 癌症患者受到高度免疫抑制，从腹水中分离出的T细胞表达了很多 抑制标记；使这项研究非常相关，因为最近针对卵巢T细胞的临床试验 癌症还没有成功。因此，总体假设指出，应力激素抑制抗肿瘤 T细胞反应；因此，通过药理学方法阻断将增强T细胞功能并提高功效 卵巢癌检查点抑制疗法。特定目标1将表征免疫学变化 肾上腺素能信号对卵巢癌患者的细胞因子和T细胞反应具有。在特定的目标2中， 研究团队将通过临床前模型来确定每日约束应力对T细胞功能的影响 用抗PD-1治疗和普萘洛尔治疗的卵巢癌。研究团队相信该建议将 提供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，导致疾病进展。结果 提案将确定反应的免疫签名，并为旨在防止的干预措施提供理由 并治疗卵巢癌患者所经历的慢性压力，其最终目的是改善临床 对检查点阻滞疗法的反应。 OMB No. 0925-0001/0002（修订版01/18通过03/31/2020批准）页面延续格式页面