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.

在本提案中提出的新数据中，项目摘要 - 提取，我们表明神经驱动，通过β-肾上腺素受体（β-ARS）通过肾上腺应激信号传导抑制对检查点的反应性在两个不同的可移植肿瘤模型中抑制剂治疗。通过使用三个降低β-ar信号传导单独的方法（包括使用温暖的室温，药物拮抗剂在β-ars和β-ar敲除小鼠的范围内，我们观察到了免疫微环境的显着重塑肿瘤。从肿瘤微环境（TME）中，大大没有CD8+ T细胞，TME变得富含T细胞，激活的CD8+细胞与Treg细胞的比率增强了，我们与改进的变化对抗PD-1检查点疗法的敏感性。其他新的机械数据表明β-AR信号传导抑制最佳T细胞激活所需的代谢重编程。这些以及其他新颖的数据提高了挑衅性的假设是减少TME中肾上腺素信号传导的挑衅性假设（通过重新利用安全和良好研究烟草β受体阻滞剂）可以显着提高患者对免疫疗法的总体反应率。到严格将这些数据扩展到其他肿瘤模型，并确定所涉及的机械途径，这项修订的建议概述了一套全面的实验，这些实验将提供深入的理解肾上腺应激信号如何显着和广泛影响基线免疫，最终是对免疫疗法的反应。提出了三个互动目的：AIM 1将检验肾上腺应力信号传导影响的假设致癌或遗传学诱导的自围候肿瘤模型的肿瘤形成或进展操纵宿主和肿瘤在长时间内共同演变。这些实验提供独特的机会来研究宿主免疫细胞之间相互作用的同等阶段和肿瘤细胞。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的效率检查点抑制剂。在AIM 2中，我们将定义肾上腺压力如何影响 TME。 AIM 3来自我们的新机械数据，表明肾上腺信号抑制了生物能量 CD8+ T细胞激活和效应子函数所需的更改。由于代谢重编程是最佳T细胞介导的抗肿瘤免疫反应所必需的，减少肾上腺应激可能会提供我们研究中看到的肾上腺应激信号传导的广泛作用的一种新型机制。影响：这些数据突出了肾上腺应激信号传导调节免疫状态的潜力肿瘤微环境并支持患者临床上可用的β受体阻滞剂的战略性重新利用改善对免疫疗法的反应。