The impact of chronic stress on radiation induced cell death and the anti-tumor immune response

慢性应激对辐射诱导的细胞死亡和抗肿瘤免疫反应的影响

基本信息

批准号：
10688044
负责人：
Cameron Riker Macdonald
金额：
$ 5.27万
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：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688044
关键词：
Address Adenosine Adrenergic Agents Affect Agonist Antigens Anxiety Apoptosis Automobile Driving Biological Bone Marrow CD8-Positive T-Lymphocytes Cancer Patient Catabolism Cell Death Cell Death Induction Cell Death Process Cell Line Cell Maturation Cell Survival Cell physiology Cells Cessation of life Chronic Chronic stress Clinical Clinical Research Coculture Techniques Cultured Tumor Cells Cyclic AMP Data Dendritic Cells Distant Dose Enzymes Event Future Generations Genetic Goals Granulocyte-Macrophage Colony-Stimulating Factor Guidelines HMGB1 gene Human Immune Immune response Immunologic Stimulation Immunologics Impairment Implant In Vitro Innate Immune Response Irradiated tumor Isoproterenol Lead Malignant Neoplasms Measures Mediating Molecular Mouse Strains Mus Necrosis Neoplasm Metastasis Neurotransmitters Norepinephrine Pathway interactions Patient-Focused Outcomes Patients Pattern Phagocytosis Physiological Play Process Production Proliferating Propranolol Publishing Quality of life Radiation Radiation Dose Unit Radiation therapy Regimen Research Resistance Role Series Signal Induction Signal Pathway Signal Transduction Stimulator of Interferon Genes Stress Sympathetic Nervous System T-Cell Activation Technology Testing Time Tumor Antigens Tumor Cell Line Tumor Immunity adaptive immunity adrenergic stress antagonist anti-tumor immune response antigen detection beta-adrenergic receptor calreticulin cancer cell cancer therapy cell injury cell type cytokine experience experimental study genetic approach immune activation immunogenic immunogenic cell death improved in situ vaccine in vivo interest irradiation knock-down lymph nodes migration neoplastic cell novel pharmacologic radiation effect radiation resistance radiation response receptor recruit response stress reduction therapy resistant trafficking tumor tumor microenvironment

项目摘要

Radiation Therapy (RT) is a common form of cancer treatment that can be effective in treating numerous malignancies. Two key components of an effective RT regimen are a dose of irradiation that is sufficient to cause tumor cell death, and an innate immune response, driven by dendritic cells and fueled by the debris from dying tumor cells, that goes on to activate anti-tumor adaptive immunity. Collectively, this process has come to be known as the in situ vaccine effect of radiation. Unfortunately for many patients, a deficiency in one of these two key components can occur from the onset of treatment, or develop over time, and result in resistance to RT. For example, if an insufficient amount of tumor cell death occurs from a given dose of radiation, not only will more live cancer cells remain within the tumor, but this lack of cell death will also ultimately limit the activation and recruitment of adaptive immune cells. Without adaptive immune activation, the remaining live cells within the tumor, and potential metastases that could be present throughout the body, can survive and proliferate. We have determined that chronic stress mediated by β-adrenergic signaling is capable of inducing tumor cell resistance to irradiation induced cell death in vitro, and we have also determined that this same stress results in a subdued anti-tumor immune response generated from RT in vivo. The goal of this proposal is to resolve the mechanism through which adrenergic stress induces tumor cell radioresistance, and to determine whether this change in cell death is driving the immunologic changes observed in vivo, in addition to the direct effects of stress on immune cells. To address these goals, we will use pharmacologic and genetic approaches to induce or inhibit signaling cascades downstream of the β1, β2, and β3-ARs, and determine which receptor, and which signaling pathways, are responsible for the observed increase in tumor cell survival after irradiation. We will define how this signaling drives survival by evaluating cell death pathways including apoptosis, necrosis, and necroptosis, and determine whether inhibiting this signaling also leads to a potentially more immune stimulating tumor microenvironment. To do so, we will assess cGAS/STING signaling and damage associated molecular pattern (DAMP) production (including ATP, HMGB1, and Calreticulin) in vitro. Using a series of co-culture experiments where dendritic cells (DCs) are cultured with irradiated tumor cells experiencing varying levels of β-AR signaling, we will evaluate whether changes in the radiation induced cell death processes described above affect DC maturation and function. In vivo, we will utilize various β-AR deficient mouse strains to evaluate whether increased β-AR signaling in tumor cells alone is sufficient to drive resistance to therapy and impaired anti-tumor immunity. Changes in DAMP production in vivo will also be evaluated. Taken together, this project has the potential to produce paradigm shifting discoveries which outline a new and important mechanism of radiation resistance that is driven by the human physiologic response to chronic stress and anxiety, β-adrenergic signaling. Ultimately, these discoveries could enhance the efficacy RT, improve patient outcomes, and increase patient quality of life.

放射疗法（RT）是一种常见的癌症治疗形式，可以有效治疗众多恶性肿瘤。有效的RT方案的两个关键组成部分是辐照剂量，足以引起肿瘤细胞死亡和先天免疫反应，由树突状细胞驱动，并由碎屑燃烧肿瘤细胞，继续激活抗肿瘤适应性免疫（by）。总的来说，这个过程已经开始称为辐射的原位疫苗效应。不幸的是，对于许多患者来说，这两个患者缺乏关键成分可以从治疗的开始或随着时间的流逝而发展，并导致对RT的耐药性。例如，如果从给定剂量的辐射剂量发生的肿瘤细胞死亡不足，不仅会更多活癌细胞保留在肿瘤内，但是缺乏细胞死亡也将最终限制激活和募集自适应免疫细胞。没有自适应免疫激活，其余的活细胞在肿瘤以及可能存在于整个体内的潜在转移酶可以生存和增殖。我们有确定由β-肾上腺肾上腺素信号传导介导的慢性应激能够诱导肿瘤细胞抗性辐照在体外诱导细胞死亡，我们还确定了这种相同的应力导致柔和 RT体内产生的抗肿瘤免疫传感器。该提议的目的是解决机制肾上腺应激诱导肿瘤细胞辐射，并确定细胞的这种变化是否死亡正在推动体内观察到的免疫学变化，除了压力对免疫的直接影响细胞。为了解决这些目标，我们将使用药物和遗传方法来诱导或抑制信号传导 β1，β2和β3-ARS下游的级联反应，并确定哪个受体以及哪些信号通路，负责观察到的肿瘤细胞存活后的增加。我们将定义该信号如何通过评估包括凋亡，坏死和坏死的细胞死亡途径来驱动生存，并确定是否抑制这种信号传导也会导致潜在的免疫刺激肿瘤微环境。到这样做，我们将评估CGA/STING信号传导和相关分子模式的损伤（包括ATP，HMGB1和钙网蛋白）体外。使用一系列共培养实验，其中树突状细胞（DC）用辐照的肿瘤细胞培养，经历不同水平的β-AR信号传导，我们将评估辐射引起的细胞死亡过程的变化是否影响直流成熟和功能。在体内，我们将利用各种β-AR缺乏小鼠菌株来评估是否增加β-ar 仅肿瘤细胞中的信号传导就足以促进对治疗的抵抗力和抗肿瘤免疫史的损害。还将评估体内潮湿产生的变化。综上所述，这个项目有可能产生范式变化的发现，该发现概述了一种新的重要机制，其耐药性机制由人类对慢性应激和焦虑，β-肾上腺素能信号传导的生理反应驱动。最终，这些发现可以提高效率RT，改善患者的结果并提高患者的生活质量。