Quantitatively modeling immune responses to cancer

定量模拟癌症免疫反应

• 批准号: 9355725
• 负责人: Matthew Spitzer
• 金额: $ 39.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355725
• 关键词: Adenocarcinoma; Allogenic; Autoimmunity; Behavior; Cancer Patient; Cataloging; Catalogs; Cells; Clinic; Clinical; Computing Methodologies; Decentralization; Decision Making; Development; Environment; Failure; Goals; Human; Immune; Immune response; Immune system; Immunologic Receptors; Immunological Models; Immunologics; Immunotherapy; Impairment; Individual; Infection; Knowledge; Lead; Leukocytes; Ligands; Ligation; Malignant Neoplasms; Measures; Methods; Modeling; Mus; Neoplasm Metastasis; Organism; Pathway interactions; Persons; Preventive vaccine; Process; Receptors, Antigen, B-Cell; Shapes; Signal Transduction; Stimulus; Transplantation; Tumor Burden; Vaccines; Work; cancer cell; cancer immunotherapy; cytokine; effective therapy; experience; immune activation; killings; mouse model; neoplasm immunotherapy; neoplastic cell; personalized immunotherapy; preclinical study; response; success; tool; tumor; tumor immunology

PROJECT SUMMARY/ABSTRACT The immune system is a decentralized network of diverse white blood cells that is distributed across the entire organism. Contributing to its complexity, the immune system has developed mechanisms by which it remembers its prior experiences and is influenced by them. Recently, strategies to activate the immune system of cancer patients to recognize and eliminate tumor cells have resulted in significant clinical progress. These immunotherapies attempt to initiate new, potent immune responses in individuals with tumor burden. While inspiring, the majority of cancer patients do not respond to these therapies, especially those with adenocarcinomas, which are the most prevalent forms of cancer. Thus, there is a pressing need to understand why these therapies often fail and use this knowledge to develop more effective strategies. One of the major barriers to accomplishing this goal is our poor understanding of how the state of the immune system differs in cancer patients compared to healthy individuals. While it is well appreciated that tumors actively evade immune responses, we still do not understand how this context shapes the ability of the immune system to initiate and execute new responses. This gap in our knowledge has partially resulted from insufficient methods to measure and interpret the immune state. However, we have recently developed experimental and computational methods capable of modeling the state of the immune system under any condition, identifying how its behavior differs from the healthy setting. Therefore, in this proposal, we plan to apply these tools to provide a comprehensive assessment of the immune state in tumor-bearing individuals. We will begin by understanding how the immune system adapts its organization and behavior across the body during the development and spread of a tumor. We will subsequently assess how immune cells that have experienced tumor burden change their propensity to respond to new stimuli, including molecules that have potential as immunotherapies. Lastly, we will reveal how the immune system responds differently to new challenges in healthy versus tumor-bearing individuals. The result of these studies will be a comprehensive understanding of how the experience of a tumor alters the behavior of the immune system. This knowledge will be essential for the development of new immunotherapies for cancer by revealing which pathways of immune activation remain functional or become enhanced in tumor-bearing individuals. Moreover, this proposal will reveal mechanisms by which the immune system incorporates its prior knowledge when making decisions with broad implications for all immunological processes including those in infection, autoimmunity and transplantation.

项目概要/摘要 免疫系统是一个由多种白细胞组成的分散网络，分布在整个系统中。 生物。免疫系统发展出一些机制，使其变得复杂起来。 记住以前的经历并受到它们的影响。最近，激活免疫系统的策略 癌症患者识别和消除肿瘤细胞的研究取得了重大的临床进展。这些 免疫疗法试图在患有肿瘤的个体中引发新的、有效的免疫反应。尽管 令人鼓舞的是，大多数癌症患者对这些疗法没有反应，尤其是那些患有癌症的患者 腺癌，这是最常见的癌症形式。因此，迫切需要了解 为什么这些疗法经常失败，并利用这些知识来制定更有效的策略。主要之一 实现这一目标的障碍是我们对免疫系统的状态如何不同的了解不足。 癌症患者与健康人相比。尽管人们普遍认识到肿瘤会主动逃避 免疫反应，我们仍然不明白这种背景如何塑造免疫系统的能力 发起并执行新的响应。我们知识上的差距部分是由于方法不足造成的 测量和解释免疫状态。然而，我们最近开发了实验性和 能够模拟任何条件下免疫系统状态的计算方法，识别 它的行为与健康环境有何不同。因此，在本提案中，我们计划将这些工具应用于 对荷瘤个体的免疫状态进行全面评估。我们将从 了解免疫系统如何在整个身体内调整其组织和行为 肿瘤的发展和扩散。随后我们将评估免疫细胞如何经历 肿瘤负荷改变了他们对新刺激做出反应的倾向，包括具有潜力的分子 免疫疗法。最后，我们将揭示免疫系统如何以不同的方式应对新的挑战 健康个体与携带肿瘤的个体。这些研究的结果将是对 肿瘤的经历如何改变免疫系统的行为。这些知识对于 通过揭示哪些免疫激活途径仍然存在，开发新的癌症免疫疗法 在携带肿瘤的个体中功能增强或增强。此外，该提案将揭示机制 免疫系统在做出具有广泛影响的决策时会结合其先验知识 适用于所有免疫过程，包括感染、自身免疫和移植中的免疫过程。