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.

项目概要 越来越多的证据表明慢性压力与卵巢癌的进展有关。 化疗和其他创伤性生活事件可能导致心理状态改变，例如慢性压力。 具体来说，慢性压力会诱导交感神经系统持续激活并调节 不同系统（包括免疫系统）的生理反应会导致慢性压力。 释放应激激素、去甲肾上腺素和肾上腺素，已知可重新分配 T 细胞，抑制 CD8+ T- 该研究小组的初步数据表明，腹水衍生的 CD4+ 细胞。 CD8+ T 细胞表达不同的激活和抑制受体模式。 数据显示，肾上腺素对卵巢癌患者腹水来源的 T 细胞的刺激减少 颗粒酶 B 表达，表明 CD8+ T 细胞功能下降。此外，该团队的初步数据。 研究表明，日常束缚压力显着增加了各种小鼠模型中卵巢癌的生长 因此，该提案旨在描述应激激素如何导致卵巢免疫抑制。 癌症微环境以及这种免疫抑制如何降低抗 PD-1 治疗效果。 研究小组的总体假设是，应激激素会抑制抗肿瘤 T 细胞反应，从而阻断 T 细胞的反应； 通过药理学方法的肾上腺素信号传导将增强 T 细胞功能并提高 PD-1 的功效 卵巢癌检查点抑制疗法的具体目标 1 将表征肾上腺素能的作用。 CD4+ 和 CD8+ T 细胞的信号传导激活/耗尽标记物的表达变化、肿瘤识别和 CD8+ T 细胞的杀伤能力。 具体目标 2 将决定日常束缚应激和普萘洛尔的效果。 卵巢癌同基因小鼠模型中抗 PD-1 治疗效果和 T 细胞生物学的研究。 实验旨在提供一种全面的方法来阐明肾上腺素信号传导对 T 细胞的作用 该提案产生的功能、肿瘤突变负荷和检查点抑制治疗效果的数据。 将支持针对应激激素介导的途径来改善卵巢对免疫治疗的反应 这项研究的长期目标是提供有关卵巢潜在预测生物标志物的见解。 癌症患者对免疫疗法的反应，以及努力预防和治疗慢性压力对免疫疗法的影响 患者同时改善对检查点抑制疗法的临床反应。