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

• 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
• 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

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，可以有效地治疗许多癌症。 恶性肿瘤有效的RT方案的两个关键组成部分是足以引起 肿瘤细胞死亡，以及由树突细胞驱动并由死亡碎片提供燃料的先天免疫反应 肿瘤细胞，进而激活抗肿瘤适应性免疫。总的来说，这一进程已经成为 被称为辐射的原位疫苗效应。不幸的是，对许多患者来说，这两种疾病之一的缺乏 关键成分可以在治疗开始时出现，或随着时间的推移而发展，并导致对RT的耐药性。 例如，如果给定剂量的辐射发生的肿瘤细胞死亡量不足， 活的癌细胞保留在肿瘤内，但这种细胞死亡的缺乏也将最终限制癌细胞的激活， 适应性免疫细胞的募集。如果没有适应性免疫激活， 肿瘤和可能存在于全身的潜在转移可以存活和增殖。我们有 确定由β-肾上腺素能信号传导介导的慢性应激能够诱导肿瘤细胞抵抗 辐射诱导的细胞死亡，我们也已经确定，这种相同的压力会导致一种抑制的细胞死亡。 在体内由RT产生的抗肿瘤免疫应答。这项提案的目标是解决机制 肾上腺素能应激诱导肿瘤细胞辐射抗性的机制，并确定这种变化是否在细胞内引起了肿瘤细胞的辐射抗性。 除了应激对免疫系统的直接影响外，死亡还驱动着体内观察到的免疫学变化。 细胞为了实现这些目标，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下游的级联反应，并决定哪种受体，哪种信号通路， 是辐射后观察到的肿瘤细胞存活率增加的原因。我们将定义这个信号 通过评估细胞死亡途径（包括凋亡、坏死和坏死性凋亡）来驱动存活，并确定 抑制这种信号传导是否也会导致潜在的更多的免疫刺激肿瘤微环境。到 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、HMGB 1和钙网蛋白）。使用一系列共培养实验， (DCs)与经历不同水平β-AR信号传导的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影响DC成熟， 功能在体内，我们将利用各种β-AR缺陷小鼠品系来评估是否增加β-AR 单独的肿瘤细胞中的信号传导足以驱动对治疗的抗性和受损的抗肿瘤免疫。 还将评价体内DAMP产生的变化。总的来说，这个项目有可能 产生范式转变的发现，概述了一个新的和重要的抗辐射机制， 是由人类对慢性压力和焦虑的生理反应，β-肾上腺素能信号传导驱动的。最后， 这些发现可以增强RT的功效，改善患者的结果，并提高患者的生活质量。