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: 10355862
• 负责人: GUILLERMO N ARMAIZ-PENA
• 金额: $ 8.53万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355862
• 关键词: Adjuvant; Adrenergic Agents; Ascites; CD8-Positive T-Lymphocytes; Cancer Patient; Cell physiology; Cellular biology; Chronic stress; Clinical; Clinical Trials; Data; Disease model; Epinephrine; Event; Functional disorder; Goals; Granzyme; Growth; Hormones; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunotherapy; Impairment; Lead; Life; Link; Longitudinal Studies; Malignant neoplasm of ovary; Mediating; Methods; Mutation; Norepinephrine; Pathway interactions; Patients; Pattern; Pharmacology; Physiological; Prognosis; Propranolol; Reporting; Role; Signal Transduction; Stress; Sympathetic Nervous System; System; T cell response; T-Lymphocyte; Treatment Efficacy; anti-PD1 therapy; cancer diagnosis; checkpoint inhibition; checkpoint therapy; chemotherapy; exhaustion; experimental study; immunogenicity; immunosuppressed; improved; insight; mouse model; ovarian neoplasm; patient response; predictive marker; prevent; programmed cell death protein 1; psychologic; receptor; response; restraint stress; tumor; tumor microenvironment; tumor progression

PROJECT SUMMARY There is growing evidence that links chronic stress to ovarian cancer progression. Cancer diagnosis, chemotherapy, and other traumatic life events can lead to altered psychological states such as chronic stress. Specifically, chronic stress induces sustained activation of the sympathetic nervous system and modulates physiological responses across different systems, including the immune system. Chronic stress results in the release of stress hormones, norepinephrine, and epinephrine known to redistribute T-cells, suppress CD8+ T- cells, and lead to worse prognoses. Preliminary data from this study team suggests that ascites-derived CD4+ and CD8+ T-cells express a heterogeneous pattern of activation and inhibitory receptors. Additionally, the team’s data showed that epinephrine stimulation of ascites-derived T-cells from ovarian cancer patients decreased Granzyme B expression, suggesting a decrease in CD8+ T-cell function. Moreover, the team’s preliminary data showed that daily restraint stress significantly increased ovarian cancer growth in various mouse models of disease. Hence, this proposal aims to characterize how stress hormones lead to an immunosuppressed ovarian cancer microenvironment and how this immunosuppression may decrease anti-PD-1 treatment efficacy. The study team’s overall hypothesis is that stress hormones suppress anti-tumor T-cell responses; thus, blockade of adrenergic signaling by pharmacologic methods will enhance T-cell function and improve the efficacy of PD-1 checkpoint inhibition therapy in ovarian cancer. Specific Aim 1 will characterize the effects of adrenergic signaling on CD4+ and CD8+ T-cell expression changes of activation/exhaustion markers, tumor recognition, and killing capacity of CD8+ T-cells. Specific Aim 2 will determine the effect of daily restraint stress and propranolol on anti-PD-1 treatment efficacy and T-cell biology in syngeneic mouse models of ovarian cancer. The proposed experiments aim to provide a comprehensive approach to elucidate the role of adrenergic signaling on T-cell function, tumor mutational burden, and checkpoint inhibition therapy efficacy. Data resulting from this proposal will support targeting stress hormone-mediated pathways to improve responses to immunotherapy in ovarian cancer patients. This study's long-term goal is to provide insight on potential predictive biomarkers of ovarian cancer patients’ response to immunotherapies with efforts to prevent and treat the effect of chronic stress on patients while improving clinical responses to checkpoint inhibition therapy.

项目摘要 越来越多的证据将慢性应激与卵巢癌的进展联系起来。癌症诊断， 化学疗法和其他创伤性生活事件可能会导致心理状态改变，例如慢性压力。 具体而言，慢性应激会引起交感神经系统的持续激活并调节 跨不同系统（包括免疫系统）的生理反应。慢性压力导致 释放应力激素，去甲肾上腺素和肾上腺素已知是重新分布T细胞的，抑制CD8+ T-- 细胞，并导致预后较差。该研究团队的初步数据表明，腹水衍生的CD4+ CD8+ T细胞表达了激活和抑制受体的异质模式。此外，团队的 数据表明，卵巢衍生的T细胞的肾上腺素刺激来自卵巢癌患者 颗粒酶B表达，表明CD8+ T细胞功能降低。而且，团队的初步数据 表明每日约束应力在各种小鼠模型中显着增加卵巢癌的生长 疾病。因此，该提议旨在表征压力激素如何导致免疫抑制的卵巢 癌症微环境以及这种免疫抑制如何降低抗PD-1治疗效率。这 研究团队的总体假设是，压力恐怖措施抑制了抗肿瘤的T细胞反应。因此，块 药物学方法的肾上腺信号传导将增强T细胞功能并提高PD-1的效率 卵巢癌的检查点抑制疗法。特定目标1将表征肾上腺素的影响 在CD4+和CD8+ T细胞表达激活/耗尽标记，肿瘤识别和 CD8+ T细胞的杀伤能力。特定的目标2将确定每日约束应力和普萘洛尔的影响 关于卵巢癌的合成小鼠模型的抗PD-1治疗效率和T细胞生物学。提议 实验旨在提供一种全面的方法，以阐明肾上腺信号在T细胞中的作用 功能，肿瘤突变烧伤和检查点抑制疗法的有效性。该提案产生的数据 将支持靶向靶向应力同源介导的途径，以改善卵巢免疫疗法的反应 癌症患者。这项研究的长期目标是洞悉卵巢的潜在预测生物标志物 癌症患者对免疫疗法的反应，以防止和治疗慢性应激对 患者在改善对检查点抑制疗法的临床反应的同时。