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

项目摘要-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-ARs)的肾上腺素能应激信号抑制对检查点的反应 两种不同的可移植肿瘤模型中的抑制物治疗。通过使用以下三种方法减少β-AR信令 不同的方法，(包括通过使用更温暖的室温，药理拮抗剂 β-AR和β-AR基因敲除小鼠)，我们观察到免疫微环境的显著重塑 肿瘤。从基本上缺乏CD8+T细胞的肿瘤微环境(TME)，TME变得富含T细胞， 随着激活的CD8+细胞与Treg细胞比率的提高，这一变化与我们改善的 对抗PD-1检查点治疗的敏感性。其他新的机械性数据显示，β-AR信号 抑制最佳T细胞激活所需的代谢重编程。这些，以及其他新的数据，引发了 一种挑衅性的假设是，减少TME中的肾上腺素能信号(通过重新调整安全和良好的用途- 研究的β阻滞剂)可以显著提高患者对免疫治疗的总体应答率。至 将这些数据严格扩展到更多的肿瘤模型，并确定涉及的机制路径， 这份修订后的提案概述了一套全面的实验，将提供一个深入的理解 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， 对免疫治疗的反应。 提出了三个交互目标：目标1将检验肾上腺素能应激信号影响 致癌物和遗传因素诱发的自体肿瘤模型中肿瘤的形成和发展 宿主和肿瘤在很长一段时间内一起进化的操作。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。利用这些模型，我们还将测试β阻滞剂是否可以提高免疫效果 检查点抑制药。在目标2中，我们将定义肾上腺素应激如何影响小鼠的免疫环境 我也是。目标3源于我们新的机制数据，表明肾上腺素能信号抑制生物能量 CD8+T细胞激活和效应器功能所需的变化。因为新陈代谢重新编程 需要最佳的T细胞介导的抗肿瘤免疫反应，减少肾上腺素能应激可以提供 在我们的研究中发现了肾上腺素能应激信号产生广泛影响的新机制。 影响：这些数据突出了肾上腺素应激信号调节机体免疫状态的潜力。 肿瘤微环境和支持临床上可用β阻滞剂的战略性再利用 以提高对免疫治疗的反应。

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.