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

方案主任/首席调查员(最后、第一、中间)：Armaiz-Pena，Guillermo N. 项目总结 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 对卵巢癌患者的负面影响。多项研究报告称，卵巢癌患者患有 在诊断后和治疗过程中增加了心理痛苦，这导致病情恶化 生活质量和总体存活率下降。这些改变的心理状态被认为与 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增加， 以及动物模型中卵巢癌的进展。另一方面，肾上腺素能信号如何影响抗 肿瘤免疫反应仍然知之甚少。这项建议表明，来自卵巢的腹水 癌症患者高度免疫抑制，从腹水中分离的T细胞表达丰富的 抑制性标记物；使这项研究与最近针对卵巢T细胞的临床试验极其相关 癌症并没有成功。因此，总体假说认为应激激素抑制抗肿瘤作用。 T细胞反应；因此，用药物方法阻断将增强T细胞功能，提高疗效 检查点抑制疗法在卵巢癌中的应用。特定目标1将描述免疫变化的特征 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， 研究小组将通过临床前模型确定每日束缚应激对T细胞功能的影响 抗PD-1治疗与心得安联合治疗卵巢癌。研究小组相信，这项建议将 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， 如T细胞功能和检查点抑制效果，导致疾病进展。由此产生的结果 该提案将确定反应的免疫特征，并为旨在预防的干预提供理由 以及治疗卵巢癌患者经历的慢性应激，最终目标是改善临床 对检查点封锁治疗的反应。 OMB编号0925-0001/0002(01/18修订版批准至2020年3月31日)页面续格式页面