Integrating systems immunology with immunometabolism and cancer immunity

将系统免疫学与免疫代谢和癌症免疫相结合

• 批准号: 10657475
• 负责人: Hongbo Chi
• 金额: $ 105.55万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657475
• 关键词: Algorithms; Area; Biological Process; CRISPR screen; Cells; Cellular Metabolic Process; Dendritic Cells; Development; FRAP1 gene; Foundations; Goals; Heterogeneity; Homeostasis; Immune; Immune signaling; Immunity; Immunology; Immunooncology; Inflammation; Link; Malignant Childhood Neoplasm; Malignant Neoplasms; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Nutrient; Pathway interactions; Positioning Attribute; Principal Investigator; Process; Program Description; Proteomics; Research; Signal Transduction; System; Systems Biology; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Tumor Immunity; Work; adaptive immune response; bench-to-bedside translation; cancer immunotherapy; cancer therapy; clinical development; clinical translation; experience; human disease; immune function; improved; in vivo; innovation; insight; interdisciplinary approach; novel; pre-clinical; programs; rapid growth; refractory cancer; stemness; tumor microenvironment

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.

项目描述/摘要 新陈代谢是基本上所有生物功能的核心过程。我们研究计划的目标 是发现免疫细胞代谢状态与组织稳态之间的联系机制 抗肿瘤免疫力，并利用这些见解来开发更好的癌症治疗方法。我们接近这些 通过整合假设驱动和系统免疫学方法来提出问题，我们的工作产生了 三个主要领域的创新。首先，我们揭示了T细胞命运、状态的代谢重编程原理 和宽容。我们早期在 T 细胞命运和状态的代谢控制方面的发现，包括 T 细胞亚群特异性 Warburg 代谢和 mTOR 信号传导的需求，促成了 免疫代谢领域。最近，我们发现了 T 细胞命运的体内代谢异质性 肿瘤微环境和炎症的干性和终末分化之间的关系，以及循环 代谢静止和免疫发育和功能中存在静止。其次，我们定义了 营养和免疫信号传导机制。我们确定了营养和自噬信号如何发挥作用 细胞代谢的有效调节剂，以及树突状细胞衍生的免疫和代谢信号如何 由T细胞整合。第三，我们将传统的假设驱动或“还原论”方法与 系统生物学原理，包括内部开发的网络算法NetBID，体内汇集 CRISPR 筛选和系统蛋白质组学，导致新概念和“隐藏的”的识别 免疫代谢中的驱动因素无法从更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成为可能，并为临床转化提供了明确的途径 儿童癌症的创新疗法。我们的系统免疫学策略提供功能性- 相关的发现平台，以支持免疫和癌症代谢控制的未来研究。 具体来说，未来的研究计划将解决免疫代谢和免疫代谢中的三个基本问题 抗肿瘤免疫，通过检验免疫代谢途径密不可分的中心假设 与适应性免疫反应和抗肿瘤免疫机制有关；通过了解这些 联系，我们获得了治疗癌症的新目标：1）如何感知营养信号并 被免疫细胞整合？ 2）如何重新调整免疫代谢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？我们将重点关注癌症免疫治疗的基石 T 细胞，以获得深入的见解，但我们 预计这些发现可以被测试并扩展到其他免疫细胞。我们的应用经验 多学科方法，结合我们新开发和使用的新型临床前和人类药物 癌症免疫治疗的疾病系统，使我们处于独特的地位，能够产生根本性的发现 通过重新编程代谢途径进行癌症治疗的免疫代谢和临床转化。