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

• 批准号: 10306360
• 负责人: ELIZABETH A REPASKY
• 金额: $ 55.58万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-19 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306360
• 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; antagonist; 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

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.

项目总结-摘要在本提案中提出的新数据中，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传导抑制对检查点的反应性 在两种不同的可移植肿瘤模型中的抑制剂治疗。通过使用三种方法减少β-AR信号， 单独的方法，（包括通过使用更温暖的室温，药理学拮抗剂， β-AR和β-AR基因敲除小鼠），我们观察到小鼠免疫微环境的显着重塑。 肿瘤的从基本上缺乏CD 8 + T细胞的肿瘤微环境（TME），TME变得富含T细胞， 随着活化的CD 8+细胞与Treg细胞的比例增加，我们将这种变化与改善的 抗PD-1检查点治疗的敏感性。其他新的机制数据表明，β-AR信号 抑制最佳T细胞活化所需的代谢重编程。这些以及其他新数据， 刺激性的假设，减少肾上腺素能信号在TME（通过重新利用安全和良好的， 研究的β-受体阻滞剂）可以显著增加患者对免疫疗法的总体应答率。到 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， 这份修订后的提案概述了一套全面的实验，这些实验将提供对 肾上腺素能应激信号如何显著和广泛地影响基线免疫，最终， 对免疫疗法的反应。 提出了三个相互作用的目标：目标1将检验肾上腺素能应激信号影响 致癌物或遗传物质诱导的原位肿瘤模型中的肿瘤形成或进展 在一个实施方案中，所述方法包括操作，其中宿主和肿瘤在延长的时间段内一起进化。这些实验 为研究宿主免疫细胞之间相互作用的平衡阶段提供了独特的机会 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治疗的疗效。 检查点抑制剂。在目标2中，我们将定义肾上腺素能应激如何影响机体的免疫结构。 TME。目的3来自我们的新的机制数据，表明肾上腺素能信号抑制生物能信号。 CD 8 + T细胞活化和效应子功能所需的变化。由于代谢重编程是 最佳的T细胞介导的抗肿瘤免疫反应所需的，减少肾上腺素能应激可以提供 在我们的研究中发现了一种新的肾上腺素能应激信号传导的广泛作用机制。 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，并支持临床可用β受体阻滞剂在患者中的战略性再利用 来提高对免疫疗法的反应。