Integrating systems immunology with immunometabolism and cancer immunity

程序描述/摘要 新陈代谢基本上是所有生物功能的核心过程。我们研究计划的目标是 是发现将免疫细胞的代谢状态与组织动态平衡联系起来的机制 抗肿瘤免疫，并将这些见解用于开发更好的癌症治疗方法。我们的方法是 通过整合假设驱动和系统免疫学的方法来提出问题，我们的工作已经产生 三个主要领域的创新。首先，我们揭示了T细胞命运、状态的代谢重新编程的原理 和宽容。我们早期在代谢控制T细胞命运和状态方面的发现，包括T细胞亚群特异性 对Warburg新陈代谢和mTOR信号的需求，有助于建立和快速生长 免疫代谢领域。最近，我们在体内发现了决定T细胞命运的代谢异质性 肿瘤微环境中的干性和终末分化与炎症及细胞周期的关系 在免疫发育和功能过程中存在代谢停滞和停滞。第二，我们定义了 营养和免疫信号的机制。我们确定了营养和自噬信号是如何发挥作用的 细胞代谢的有效调节者，以及树突状细胞衍生的免疫和代谢信号是如何 由T细胞整合。第三，我们结合了传统的假说驱动或还原论者的方法 系统生物学原理，包括内部开发的网络算法NetBID，在体内汇集 CRISPR筛选和系统蛋白质组学，这导致了新概念的识别和隐藏 驾驶员的免疫新陈代谢不能从简单的系统中推测出来。更重要的是，这些 方法使新的免疫肿瘤学靶点的发现具有明确的临床翻译途径 儿童癌症的创新疗法。我们的系统免疫学策略在功能上提供- 相关发现平台，支持未来免疫和癌症代谢控制的研究。 具体地说，未来的研究计划将解决免疫代谢和 抗肿瘤免疫，通过测试免疫代谢途径难以解决的中心假设 与适应性免疫反应和抗肿瘤免疫的机制有关；通过理解这些 联系，我们获得了治疗癌症的新靶点：1)营养信号是如何被感知的，以及 被免疫细胞整合？2)免疫代谢如何重新连接以提高抗肿瘤免疫力？3) 我们能否打破癌症免疫和治疗的代谢障碍，特别是在治疗耐药的情况下 癌症？我们将重点关注T细胞，这是癌症免疫治疗的基石，以获得深入的见解，但我们 预计这一发现可以被测试并推广到其他免疫细胞。我们在应用程序中的经验 多学科方法，结合我们对新型临床前和人类的新开发和使用 癌症免疫治疗的疾病系统，使我们在产生基础性发现方面处于独特的地位 通过重新编程代谢途径，在免疫代谢和癌症治疗的临床翻译方面。

Program Description/Abstract Metabolism is the core process underlying essentially all biological functions. The goal of our research program is to discover the mechanisms linking the metabolic state of immune cells with tissue homeostasis and antitumor immunity, and to use these insights for development of better cancer treatments. We approach these questions by integrating hypothesis-driven and systems immunology approaches, and our work has produced innovation in three main areas. First, we revealed the principle of metabolic reprogramming for T cell fate, state and tolerance. Our earlier findings in metabolic control of T cell fate and state, including T cell subset-specific requirement of Warburg metabolism and mTOR signaling, contributed to the foundation and rapid growth of the immunometabolism field. More recently, we identified metabolic heterogeneity in vivo that underlies T cell fate between stemness and terminal differentiation in tumor microenvironment and inflammation, and the cycle of metabolic quiescence and quiescence exit in immune development and function. Second, we defined mechanisms of nutrient and immune signaling. We identified how nutrient and autophagic signals serve as potent regulators of cellular metabolism, and how dendritic cell-derived immune and metabolic signals are integrated by T cells. Third, we combined the traditional hypothesis-driven or ‘reductionist’ approach with systems biology principles, including in-house development of network algorithm NetBID, pooled in vivo CRISPR screening and systems proteomics, which led to the identification of new concepts and ‘hidden drivers’ in immunometabolism that cannot be surmised from simpler systems. More importantly, these approaches enabled the discovery of novel immuno-oncology targets with a clear path to clinical translation into innovative therapeutics for pediatric cancers. Our systems immunology strategies provide functionally- relevant discovery platforms to support future research in metabolic control of immunity and cancer. Specifically, the future research program will address three fundamental questions in immunometabolism and antitumor immunity, by testing the central hypothesis that immunometabolic pathways are inextricably connected to the mechanisms of adaptive immune responses and antitumor immunity; by understanding these connections, we gain new targets for the treatment of cancer: 1) How are nutrient signals sensed and integrated by immune cells? 2) How can immunometabolism be rewired to improve antitumor immunity? 3) Can we break metabolic barriers to cancer immunity and therapy, especially in therapeutically-resistant cancers? We will focus on T cells, the cornerstone for cancer immunotherapy, to gain in-depth insights, but we anticipate the findings can be tested and extended into other immune cells. Our experience in the application of multidisciplinary approaches, combined with our new development and use of novel preclinical and human disease systems for cancer immunotherapy, makes us uniquely positioned to produce fundamental discoveries in immunometabolism and clinical translation for cancer treatments by reprogramming metabolic pathways.