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)在脑出血中的关键作用，但在很大程度上还没有被研究过 通过去甲肾上腺素驱动的激活信号调节放射治疗(RT)的总体疗效 β-肾上腺素能受体。我们的初步数据显示，肾上腺素能应激信号钝化了对 照射后的肿瘤通过至少两条途径对RT产生影响：a)抗肿瘤免疫反应受损， 限制辐射在体内控制非辐射远处肿瘤的能力(非内窥镜效应)和b)增加 体外肿瘤细胞对辐射的内在抵抗力。这些数据支持一个令人兴奋的假设，即 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阻滞剂)相结合 显著且安全地增强肿瘤细胞对放射治疗的敏感性并刺激抗肿瘤 豁免权。我们选择了一种创新的方法来检验这一假设，在这种方法中，两个独立的 罗斯威尔公园综合癌症中心和罗切斯特大学医学中心的团队，与 辐射、应激生物学和肿瘤免疫学方面的免费专业知识将合作优化 结合RT和β阻滞剂的临床方案并确定关键的潜在细胞和分子 机械装置。目标1：检验对辐射的总体反应(在两个初选阶段)的假设 辐射肿瘤和远处的非辐射肿瘤)通过β-ARs信号来调节。我们将使用 不同品系和不同辐射条件下几种不同的临床相关肿瘤模型 协议，以确定辐射效能对β-AR信号的依赖。重要的是，我们有宝贵的 β-AR基因敲除小鼠帮助确定宿主肾上腺素能信号的作用。目标2和目标3将进行间接评估 以及肾上腺素能应激调节辐射疗效的直接机制。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 β的加入如何影响放射和免疫治疗与抗PD-1的结合- 拦截者。目标3将评估肾上腺素能应激信号是否能直接影响肿瘤的敏感性 通过改变促凋亡和抗凋亡分子的平衡或通过改变细胞对辐射和细胞毒细胞的平衡 控制肿瘤细胞对杀戮敏感性的其他途径也参与其中。 我们团队之间不断的实时信息流应该会产生优化的协议，从而增强 相信我们关于肾上腺素能信号阻断对放射治疗的影响的数据 对患者反应的预测。同时进行实验，使用不同的模型和RT 在两个不同中心的协议，将使我们能够测试更多的肿瘤模型，并增加严格性和透明度 以及我们总体结论的可重复性。总体而言，这将产生最强大的数据，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.