Understanding how adrenergic signaling influences immune contexture of tumors and the efficacy of checkpoint inhibitors

了解肾上腺素信号如何影响肿瘤的免疫环境以及检查点抑制剂的功效

基本信息

批准号：
10062481
负责人：
ELIZABETH A REPASKY
金额：
$ 56.72万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-19 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062481
关键词：
Address Adrenergic Agents Affect Attention Biochemical Bioenergetics CD8-Positive T-Lymphocytes Cancer Patient Carcinogens Cell physiology Cells Chronic Chronic stress Clinical Clinical Trials Collaborations Data Dependence Equilibrium Glycolysis Immune Immune checkpoint inhibitor Immune response Immunity Immunologist Immunotherapy Impairment Kentucky Knockout Mice Laboratory Study Laboratory mice Mediating Metabolic Metabolic Pathway Modeling Mus Neoplasm Metastasis Neoplasm Transplantation Nerve Norepinephrine Oxidative Phosphorylation Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase Phenotype Receptor Signaling Regulatory T-Lymphocyte Resistance Resources Role Shapes Signal Transduction Signaling Molecule Stress Stressful Event Sympathetic Nervous System T cell response T-Cell Activation T-Lymphocyte Temperature Testing Time Tumor Immunity Work adrenergic block adrenergic stress anti-PD-1 anti-tumor immune response arm beta-adrenergic receptor biological adaptation to stress cancer immunotherapy checkpoint therapy chemokine clinically significant cytokine epidemiology study experimental study genetic manipulation immune checkpoint blockade immunological status improved improved outcome innovation melanoma metabolomics neoplastic cell novel receptor relating to nervous system response stable isotope tumor tumor growth tumor immunology tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

PROJECT SUMMARY-ABSTRACT In new data presented in this proposal, we show that nerve driven, adrenergic stress signaling via the β-adrenergic receptors (β-ARs) inhibits responsiveness to checkpoint inhibitor therapy in two different transplantable tumor models. By reducing β-AR signaling using three separate approaches, (including through the use of a warmer room temperature, pharmacological antagonists of β-ARs, and β-AR knock out mice), we observed a significant remodeling of the immune microenvironment of tumors. From a tumor microenvironment (TME) largely devoid of CD8+ T cells, the TME became T cell rich, with an enhanced ratio of activated CD8+ cells to Treg cells, a change we associated with the improved sensitivity to anti-PD-1 checkpoint therapy. Other new, mechanistic data reveals that β-AR signaling suppresses metabolic reprogramming required for optimal T cell activation. These, and other novel data, raise the provocative hypothesis that reducing adrenergic signaling in the TME (by repurposing safe and well- studied β-blockers) could significantly increase the overall response rate of patients to immunotherapy. To rigorously expand these data to additional tumor models and to identify the mechanistic pathways involved, this revised proposal outlines a comprehensive set of experiments that will provide an in depth understanding of how adrenergic stress signaling significantly and broadly affects baseline immunity, and ultimately, the response to immunotherapy. Three interactive aims are proposed: Aim 1 will test the hypothesis that adrenergic stress signaling influences tumor formation or progression in autochthonous tumor models induced by either carcinogen or genetic manipulation wherein the host and tumor evolve together over a prolonged period of time. These experiments offer the unique opportunity to investigate the equilibrium phase of the interaction between host immune cells and tumor cells. Using these models, we will also test whether β-blockers can improve the efficacy of immune checkpoint inhibitors. In Aim 2, we will define how adrenergic stress influences the immune contexture of the TME. Aim 3 arises from our new mechanistic data showing that adrenergic signaling inhibits the bioenergetic changes required for both CD8+ T cell activation and effector function. Since metabolic reprogramming is required for an optimal T cell-mediated anti-tumor immune response, reducing adrenergic stress could provide a novel mechanism underlying the broad effects of adrenergic stress signaling seen in our studies. Impact: These data highlight the potential of adrenergic stress signaling to regulate the immune status of the tumor microenvironment and support the strategic repurposing use of clinically available β-blockers in patients to improve responses to immunotherapy.

项目摘要-摘要在本提案中提供的新数据中，我们表明神经驱动，通过 β-肾上腺素能受体 (β-AR) 的肾上腺素能应激信号抑制对检查点的反应通过使用三种减少 β-AR 信号传导，在两种不同的可移植肿瘤模型中进行抑制剂治疗。单独的方法，（包括通过使用较温暖的室温、药物拮抗剂 β-AR 和 β-AR 敲除小鼠），我们观察到免疫微环境的显着重塑从基本上缺乏 CD8+ T 细胞的肿瘤微环境 (TME) 开始，TME 变得富含 T 细胞，活化的 CD8+ 细胞与 Treg 细胞的比例增加，我们将这一变化与改善的其他新的机制数据表明 β-AR 信号转导对抗 PD-1 检查点疗法的敏感性。抑制最佳 T 细胞激活所需的代谢重编程这些以及其他新数据提出了这一点。令人兴奋的假设是减少 TME 中的肾上腺素信号传导（通过重新利用安全且良好的用途）研究的β受体阻滞剂）可以显着提高患者对免疫治疗的总体反应率。严格地将这些数据扩展到其他肿瘤模型并确定所涉及的机制途径，这个修订后的提案概述了一套全面的实验，将提供深入的理解肾上腺素能应激如何显着发出信号并广泛影响基线免疫力，最终，对免疫治疗的反应。提出了三个互动目标：目标 1 将检验肾上腺素能应激信号影响的假设由致癌物或遗传诱导的本土肿瘤模型中的肿瘤形成或进展这些实验操纵宿主和肿瘤一起进化。提供了研究宿主免疫细胞之间相互作用的平衡阶段的独特机会使用这些模型，我们还将测试β受体阻滞剂是否可以提高免疫功效。在目标 2 中，我们将定义肾上腺素能应激如何影响免疫环境。 TME。目标 3 源于我们的新机制数据，表明肾上腺素信号传导抑制生物能。由于代谢重编程是 CD8+ T 细胞激活和效应功能所需的变化。最佳 T 细胞介导的抗肿瘤免疫反应所需，减少肾上腺素能应激可以提供我们的研究中发现了肾上腺素能应激信号传导广泛影响的一种新机制。影响：这些数据强调了肾上腺素能应激信号调节免疫状态的潜力肿瘤微环境并支持临床上可用的β受体阻滞剂在患者中的战略性重新利用改善对免疫疗法的反应。