Neuroendocrine Modulation of T Cell Immunity to Cancer

T 细胞对癌症免疫的神经内分泌调节

• 批准号: 7386476
• 负责人: Todd D Schell
• 金额: $ 23.25万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386476
• 关键词: Acute; Address; Adverse effects; Animal Model; Animals; Anxiety; Area; Attention; Biochemical; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Immunity; Chronic; Chronic stress; Complex; Development; Disease; Endocrine; Epitopes; Event; Foundations; Funding Mechanisms; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunotherapeutic agent; Immunotherapy; Infiltration; Kinetics; Knowledge; Large T Antigen; Link; Malignant Neoplasms; Mediating; Modeling; Molecular; Monitor; Mus; Neurosecretory Systems; Oncogenes; Oncogenic; Pathway interactions; Patients; Positioning Attribute; Prevention therapy; Proteins; Psychological Stress; Psychoneuroimmunology; Radiosurgery; Regulation; Research; Research Personnel; Role; Series; Simian virus 40; Staging; Stress; Sympathetic Nervous System; T-Cell Activation; T-Lymphocyte; Testing; Time; Transgenic Mice; Tumor Antigens; Tumor Burden; Tumor Immunity; Tumor-Derived; Vaccines; Viral; Virus Diseases; base; body system; booster vaccine; cancer immunotherapy; cancer therapy; chemotherapy; conventional therapy; cytokine; design; experience; human subject; hypothalamic-pituitary-adrenal axis; immune function; in vivo; interest; pathogen; peptide hormone; premature; programs; psychologic; response; success; treatment strategy; tumor; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Substantial interest in harnessing the immune system as a means of therapy for cancer has arisen from both animal and human subject studies. These studies have revealed the potential benefits of triggering specific immune components, including T lymphocytes, against cancer. The success of these therapies requires a well-coordinated series of physical and biochemical events, mediated by various immune cells and cytokines. In addition, it is now widely accepted that the immune system is also subject to regulation by neuroendocrine- derived products that are associated with psychological stress, an important concern for diseases such as cancer which are associated with a high degree of anxiety. However, there is a general lack of information regarding the impact of psychological stress on T cell-based immune defenses against cancer and the neuroendocrine and immunological mechanisms that are involved. To address this issue, well-established murine models of stress-induced neuroendocrine activation and CD8+ T cell-mediated immunity to oncogene- derived tumors will be merged to embark upon a new and previously unexplored area in the field of psychoneuroimmunology. The broad objective of this R21 application is to determine the extent to which psychological stress modulates the immune response against cancer. The proposed studies will test the hypothesis that acute and/or chronic psychological stress modulates the CD8+ T cell response to a well- characterized epitope within the SV40 large T antigen oncogenic protein in transgenic mice that develop spontaneous tumors. We will investigate mechanisms by which psychological stress modulates T cell activation, differentiation and survival following recognition of the endogenous tumor antigen or an immunotherapeutic vaccine. In addition, we will assess potential mechanisms that modulate T cell accumulation within established tumors as well as T cell effector function and control of tumor progression. The rationale for the proposed research is based on the fact that a role for stress in the development and progression of cancer has been suggested and, in some cases, demonstrated, but that the precise role of the neuroendocrine-immune relationship in cancer and the mechanisms involved are not known. At the completion of this project we will expect to have broadly defined the impact of psychological stress on CD8+ T cell-based immunity to cancer and be in a strong position to design additional studies to precisely define the neuroendocrine and immunological mechanisms that can influence immunotherapeutic approaches for cancer. The studies described in this proposal provide a foundation for determining the impact of psychological stress on immune-mediated defense against cancer. An understanding of the relationship among stress, immunotherapy, and cancer will determine how patients with cancer are treated from not only a pharmacological but also a psychological perspective.

描述(申请人提供)：利用免疫系统作为治疗癌症的一种手段，已经引起了动物和人类主题研究的极大兴趣。这些研究揭示了触发包括T淋巴细胞在内的特定免疫成分对抗癌症的潜在好处。这些疗法的成功需要一系列协调良好的物理和生化事件，这些事件由各种免疫细胞和细胞因子介导。此外，现在人们普遍认为，免疫系统也受到与心理压力有关的神经内分泌衍生产品的调节，这是癌症等与高度焦虑有关的疾病的重要担忧。然而，关于心理应激对基于T细胞的抗癌免疫防御的影响及其涉及的神经内分泌和免疫机制的信息普遍缺乏。为了解决这一问题，已建立的应激诱导的神经内分泌激活和CD8+T细胞介导的肿瘤免疫模型将被合并，以进入心理神经免疫学领域的一个新的和以前未被探索的领域。这项R21应用的广泛目标是确定心理应激在多大程度上调节对癌症的免疫反应。这项拟议的研究将检验这样一种假设，即急性和/或慢性心理应激调节CD8+T细胞对自发肿瘤转基因小鼠SV40大T抗原致癌蛋白中一个特征良好的表位的反应。我们将研究在识别内源性肿瘤抗原或免疫治疗疫苗后，心理应激调节T细胞激活、分化和存活的机制。此外，我们将评估在已建立的肿瘤中调节T细胞聚集的潜在机制，以及T细胞效应器的功能和对肿瘤进展的控制。这项拟议研究的基本原理是基于这样一个事实，即已提出并在某些情况下证明了应激在癌症发生和发展中的作用，但神经内分泌-免疫关系在癌症中的确切作用和涉及的机制尚不清楚。在这个项目完成后，我们将有望广泛地定义心理压力对基于CD8+T细胞的癌症免疫的影响，并将处于有利地位，设计更多的研究，以准确定义可能影响癌症免疫治疗方法的神经内分泌和免疫机制。 这项建议中描述的研究为确定心理应激对免疫介导的抗癌防御的影响提供了基础。了解压力、免疫治疗和癌症之间的关系将决定如何从药理学和心理学的角度来治疗癌症患者。