Targeting adrenergic stress pathways to Increase tumor sensitivity to radiation and promote development of an anti-tumor immune response

我们的数据揭示了交感神经系统（SNS）在脑缺血中的重要作用， 通过去甲肾上腺素驱动的激活信号传导调节放射治疗（RT）的总体疗效 β-肾上腺素能受体。我们的初步数据表明，肾上腺素能应激信号减弱了 通过至少两种途径将照射的肿瘤进行RT：a）抗肿瘤免疫应答的损害， 限制放射在体内控制非放射性远处肿瘤（远位效应）的能力，和B）增加 肿瘤细胞对体外辐射的内在抵抗力。这些数据支持了一个令人兴奋的假设， 简单而新颖的策略，将RT与β-肾上腺素能受体（β-AR）拮抗剂（即，β受体阻滞剂） 显著且安全地增强肿瘤细胞对放射治疗的敏感性， 免疫力我们选择通过一种创新的方法来测试这一假设， 罗斯威尔公园综合癌症中心和罗切斯特大学医学中心的研究小组， 在辐射，应激生物学和肿瘤免疫学的互补专业知识将合作，以优化预- 结合RT和β受体阻滞剂的临床方案，并确定关键的潜在细胞和分子 机制等目标1：检验对辐射的总体反应（在两个主要的 辐射的肿瘤和远处的未辐射的肿瘤）通过β-AR的信号传导来调节。我们将使用 在不同品系的小鼠和不同的辐射中的几种不同和临床相关的肿瘤模型 方案，以定义辐射功效对β-AR信号传导的依赖性。重要的是，我们拥有宝贵的 β-AR基因敲除小鼠帮助确定宿主肾上腺素能信号传导的作用。目标2和3将评估间接 以及肾上腺素能应激调节辐射功效的直接机制。目标2将 评估免疫和生理因素在肿瘤微环境中的作用，包括分析 放射和免疫疗法与抗PD-1的组合如何受到β- 阻滞剂。目的3探讨肾上腺素能应激信号是否直接影响肿瘤的敏感性 通过改变促凋亡分子和抗凋亡分子的平衡， 涉及控制肿瘤细胞对杀伤的敏感性的其它途径。 我们的团队之间不断的实时信息流应该会产生优化的协议， 我们关于阻断肾上腺素能信号传导对放射治疗影响的数据， 预测患者的反应。使用不同的模型和RT进行同步实验 两个不同中心的协议，将使我们能够测试更多的肿瘤模型，并增加严谨性，透明度， 我们的总体结论的可重复性。总的来说，这将产生最强有力的数据，以促进 两个中心的大型随机研究设计。

Our data reveal a critical and largely unstudied role for the sympathetic nervous system (SNS) in regulating the overall efficacy of radiation therapy (RT), by signaling through norepinephrine-driven activation of β-adrenergic receptors. Our preliminary data reveal that adrenergic stress signaling blunts the response of the irradiated tumor to RT through at least two pathways: a) Impairment of the anti-tumor immune response, limiting the ability of radiation to control non-irradiated distant tumors (abscopal effect) in vivo and b) increasing intrinsic resistance of tumor cells to radiation in vitro. These data support the exciting hypothesis that a simple and novel strategy, combining RT with β-adrenergic receptor (β-AR) antagonists (i.e., β-blockers) significantly and safely enhances the sensitivity of tumor cells to radiation therapy and stimulates anti-tumor immunity. We have chosen to test this hypothesis by taking an innovative approach in which two separate teams, at Roswell Park Comprehensive Cancer Center and University of Rochester Medical Center, with complimentary expertise in radiation, stress biology, and tumor immunology will collaborate to optimize pre- clinical protocols combining RT with β-blockers and to identify key underlying cellular and molecular mechanisms. The aims are: Aim 1: Test the hypothesis that the overall response to radiation (in both primary irradiated tumors and distant, non-irradiated tumors) is regulated by signaling through β-ARs. We will use several different and clinically relevant tumor models in different strains of mice and different radiation protocols, to define the dependence of radiation efficacy on β-AR signaling. Importantly, we have valuable β-AR knockout mice to help pinpoint the role of host adrenergic signaling. Aims 2 and 3 will evaluate indirect and direct mechanisms by which adrenergic stress could be regulating the efficacy of radiation. Aim 2 will evaluate the role of immunological and physiological factors in the tumor microenvironment, including analysis of how combinations of radiation and immunotherapy with anti-PD-1, are influenced by the addition of β- blockers. Aim 3 will evaluate whether adrenergic stress signaling can directly influence the sensitivity of tumor cells to radiation and cytotoxic cells by altering the balance of pro-and anti-apoptotic molecules or whether other pathways that govern tumor cell sensitivity to killing are involved. A constant flow of real-time information between our teams should result in optimized protocols that enhance confidence that our data concerning the impact of blockade of adrenergic signaling on radiation therapy are predictive of patients’ response. Performing simultaneous experiments, using different models and RT protocols in two different centers, will enable us to test more tumor models, and increase rigor, transparency and reproducibility of our overall conclusions. Overall, this will produce the strongest data to facilitate the design of large randomized studies at both centers.