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.

放射治疗 (RT) 是一种常见的癌症治疗形式，可有效治疗多种癌症有效放疗方案的两个关键组成部分是足以引起癌症的照射剂量。肿瘤细胞死亡，以及由树突状细胞驱动并由死亡碎片推动的先天免疫反应肿瘤细胞，继续激活抗肿瘤适应性免疫。不幸的是，对于许多患者来说，这两种药物都缺乏其中一种。关键因素可能从治疗开始就出现，也可能随着时间的推移而发展，并导致对 RT 的耐药。例如，如果给定剂量的辐射导致的肿瘤细胞死亡量不足，不仅会导致更多的肿瘤细胞死亡。活的癌细胞保留在肿瘤内，但细胞死亡的缺乏最终也将限制激活和在没有适应性免疫激活的情况下，招募适应性免疫细胞。肿瘤以及可能存在于全身的潜在转移瘤可以存活并增殖。确定由 β-肾上腺素信号传导介导的慢性应激能够诱导肿瘤细胞抵抗体外辐射诱导的细胞死亡，我们还确定同样的压力会导致抑制该提案的目标是解决体内 RT 产生的抗肿瘤免疫反应的机制。肾上腺素能应激通过其诱导肿瘤细胞放射抗性，并确定细胞的这种变化是否除了压力对免疫的直接影响外，死亡还驱动体内观察到的免疫变化为了实现这些目标，我们将使用药理学和遗传学方法来诱导或抑制信号传导。 β1、β2 和 β3-AR 的下游级联，并确定哪个受体以及哪个信号通路，负责观察到的辐射后肿瘤细胞存活率的增加。我们将定义这种信号传导的方式。通过评估细胞死亡途径（包括细胞凋亡、坏死和坏死性凋亡）来驱动生存，并确定抑制这种信号传导是否也会导致潜在的更具免疫刺激性的肿瘤微环境。这样做，我们将评估 cGAS/STING 信号传导和损伤相关分子模式 (DAMP) 的产生（包括 ATP、HMGB1 和钙网蛋白）在体外使用一系列共培养实验，其中树突状细胞。 (DC) 与经历不同水平 β-AR 信号传导的受辐射肿瘤细胞一起培养，我们将评估上述辐射诱导的细胞死亡过程的变化是否会影响 DC 的成熟和在体内，我们将利用各种β-AR缺陷小鼠品系来评估β-AR是否增加。仅肿瘤细胞中的信号传导就足以驱动对治疗的抵抗并削弱抗肿瘤免疫力。体内 DAMP 产生的变化也将被综合评估，该项目具有潜力。产生范式转变的发现，概述了一种新的重要的抗辐射机制是由人类对慢性压力和焦虑的生理反应、β-肾上腺素信号传导驱动的。这些发现可以提高放疗的疗效、改善患者的治疗结果并提高患者的生活质量。