Neuroendocrine Modulation of T Cell Immunity to Cancer

描述（由申请人提供）：利用免疫系统作为癌症治疗手段的实质性兴趣已经从动物和人类受试者研究中产生。这些研究揭示了触发特定免疫成分（包括T淋巴细胞）对抗癌症的潜在益处。这些疗法的成功需要由各种免疫细胞和细胞因子介导的一系列协调良好的物理和生化事件。此外，现在广泛接受的是，免疫系统也受到与心理压力相关的神经内分泌衍生产物的调节，这是与高度焦虑相关的疾病如癌症的重要关注点。然而，关于心理压力对T细胞免疫防御癌症的影响以及所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，将合并已建立的应激诱导的神经内分泌激活和CD 8 + T细胞介导的对癌基因衍生肿瘤的免疫的鼠模型，以开始在心理神经免疫学领域中的新的和先前未探索的领域。这项R21应用的广泛目标是确定心理压力调节癌症免疫反应的程度。拟议的研究将检验以下假设：急性和/或慢性心理应激调节了发生自发性肿瘤的转基因小鼠中CD 8 + T细胞对SV 40大T抗原致癌蛋白内充分表征的表位的应答。我们将研究心理应激调节T细胞活化，分化和识别内源性肿瘤抗原或免疫疫苗后的存活的机制。此外，我们还将评估在已建立的肿瘤中调节T细胞积聚的潜在机制，以及T细胞效应功能和肿瘤进展的控制。这项研究的基本原理是基于这样一个事实，即压力在癌症的发展和进展中的作用已经被提出，在某些情况下，已经被证明，但神经内分泌免疫关系在癌症中的确切作用及其机制尚不清楚。在这个项目完成后，我们将期望广泛地定义心理压力对基于CD 8 + T细胞的癌症免疫的影响，并处于有利地位，以设计更多的研究来精确地定义可以影响癌症免疫方法的神经内分泌和免疫机制。 该提案中描述的研究为确定心理压力对免疫介导的癌症防御的影响提供了基础。了解压力，免疫疗法和癌症之间的关系将决定如何从药理学和心理学的角度治疗癌症患者。

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.