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

项目总结 越来越多的证据表明，慢性压力与卵巢癌的进展有关。癌症诊断， 化疗和其他创伤性生活事件会导致心理状态的改变，如慢性压力。 具体地说，慢性应激导致交感神经系统持续激活，并调节 不同系统的生理反应，包括免疫系统。慢性压力会导致 释放应激激素、去甲肾上腺素和肾上腺素，以重新分配T细胞，抑制CD8+T- 细胞，并导致更糟糕的预后。来自该研究小组的初步数据表明，腹水衍生的CD4+ CD8+T细胞表达一种不同的激活和抑制受体模式。此外，该团队的 数据显示，肾上腺素对卵巢癌患者腹水来源T细胞的刺激作用减弱 颗粒酶B表达，提示CD8+T细胞功能下降。此外，该团队的初步数据 显示每日束缚应激显著增加卵巢癌在不同小鼠模型中的生长。 疾病。因此，这项建议旨在描述压力荷尔蒙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的治疗效果。这个 研究小组的总体假设是，应激激素抑制抗肿瘤T细胞反应；因此，阻断 肾上腺素能通过药物途径增强T细胞功能，改善PD-1的疗效 卵巢癌的检查点抑制治疗。具体目标1将描述肾上腺素能 信号对CD4+和CD8+T细胞表达的激活/耗竭标志物、肿瘤识别和 CD8+T细胞的杀伤能力。特定目标2将确定每日束缚应激和心得安的效果 卵巢癌同基因小鼠模型中抗PD-1治疗效果及T细胞生物学的研究建议数 实验旨在提供一种全面的方法来阐明肾上腺素能信号在T细胞上的作用 功能、肿瘤突变负担和检查点抑制治疗效果。根据该提案得出的数据 将支持靶向应激激素介导的途径，以改善卵巢对免疫治疗的反应 癌症患者。这项研究的长期目标是为卵巢潜在的预测生物标志物提供洞察力 预防和治疗慢性应激对癌症患者免疫治疗的影响 同时改善对检查点抑制疗法的临床反应。

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.