Project 4: Interrogating and harnessing age-related IFN signaling and innate immunity in HCC prevention and therapy

项目 4：在 HCC 预防和治疗中探究和利用与年龄相关的 IFN 信号传导和先天免疫

• 批准号: 10270689
• 负责人: Gen-Sheng Feng
• 金额: $ 37.35万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270689
• 关键词: Affect; Aflatoxin B1; Age; Aging; Alcohol consumption; Cell Aging; Cell Communication; Cell physiology; Cells; Cholestasis; Chronic; Clinical Trials; Collaborations; Combination immunotherapy; Complex; DNA Damage; Data; Derivation procedure; Development; Diagnosis; Discontinuous Capillary; Disease; Double-Stranded RNA; Endothelial Cells; Epigenetic Process; Etiology; Excision; Gene Targeting; Goals; Hepatic; Hepatic Mass; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Hepatocarcinogenesis; Hepatocyte; IL6 gene; Immune; Immune checkpoint inhibitor; Immune response; Immunologics; Immunotherapeutic agent; Immunotherapy; Infection; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Injury; Interferon Type I; Interferons; Japan; Knowledge; Liver; Liver neoplasms; Malignant - descriptor; Malignant neoplasm of liver; Measures; Mediating; Metabolic; Metabolic Pathway; Modality; Modeling; Molecular; Mus; Natural Immunity; Neoplasm Metastasis; Outcome; Oxidative Stress; PD-1 blockade; PD-1/PD-L1; Pathogenicity; Patients; Play; Poly C; Poly I-C; Population; Predisposition; Prevalence; Prevention therapy; Preventive; Primary Malignant Neoplasm of Liver; Primary Neoplasm; Primary carcinoma of the liver cells; Process; Prognosis; Reporting; Resolution; Risk; Risk Factors; Role; Severities; Signal Transduction; Steatohepatitis; System; Testing; Therapeutic; Translating; Tumor Suppressor Proteins; Tumor stage; adaptive immunity; age related; aged; aging population; anti-PD-L1; base; cell type; chronic liver disease; comparative; cytokine; design; experimental study; high risk; immune function; indexing; innate immune function; insight; interdisciplinary approach; liver cancer prevention; liver function; mathematical model; mitochondrial dysfunction; mouse model; non-alcoholic fatty liver disease; novel; older patient; programmed cell death ligand 1; regenerative; resistance mechanism; response; restoration; theories; treatment strategy; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic

PROJECT SUMMARY – PROJECT 4 Primary liver cancer, mainly hepatocellular carcinoma (HCC), is now one of the most deadly malignant diseases. Aging is a high-risk factor for HCC development, although the underlying mechanisms are poorly understood. The aging liver is characterized by progressive development of an immunosuppressive microenvironment, contributed by chronic interferon (IFN) signaling, metabolic changes and altered innate and adaptive immunity. Thus, liver tumors are poorly responsive to immunotherapy. The goal of project 4 is to elucidate the roles of IFN and other inflammatory cytokines in aging-related changes of the hepatic immunological landscape. This project was prompted by our unexpected finding in most recent experiments. In dissecting molecular mechanisms of liver tumorigenesis with an inducible gene targeting system, Mx1-cre, we identified a robust tumor-inhibitory effect of polyinosinic-polycytidylic acid (polyIC), a synthetic dsRNA that induces IFN expression. These data on IFN signaling not only challenge a widely known theory of IL1a-IL6 cytokine circuit in liver tumorigenesis, but also open up new strategies for HCC immunotherapy. However, preliminary data also showed that injecting polyIC into aged mice triggered sharply different immune responses and actually aggravated HCC progression if given at late tumor stages. Thus, we hypothesize that IFN and other related inflammatory cytokines have bidirectional or paradoxical roles in HCC development, depending on ages and tumor stages. To test this hypothesis, we will extensively interrogate the roles of IFN signaling in a NASH-HCC model at single cell resolution. We will also further develop and optimize a math model and a TI (tumorigenic index) calculation system to quantitatively measure tumorigenic signal strength, tumor stages and prognosis, and also evaluate tumor-inhibitory effects of various manipulation or treatment strategies. Of note, preliminary data also showed robust induction of PD-L1 expression by polyIC in the liver, which prompted us to test a combination of polyIC and PD-L1/PD-1 blockade in treatment of liver cancer in young and old mice. We shall extensively investigate how coordinated activation of innate and adaptive immune functions can effectively suppress primary and metastatic tumor progression in the liver. Finally, we shall take advantage of newly established mouse tumor models, to systematically search for liver-specific factors and mechanisms of resistance to immunotherapy. All of the proposed experiments in this ambitious project can only be done in collaboration with Shadel, Adams and Kaech with complementary expertise and the Cores.

项目摘要 - 项目4 原发性肝癌，主要是肝细胞癌（HCC），现在是最致命的恶性疾病之一。 衰老是HCC发育的高风险因素，尽管理解的基本机制知之甚少。 肝脏衰老的特征是免疫抑制微环境的逐步发展， 由慢性干扰素（IFN）信号传导，代谢变化以及先天和适应性免疫学的贡献。 那就是肝肿瘤对免疫疗法的反应不佳。项目4的目标是阐明IFN的角色 以及其他与肝免疫局势衰老相关变化的炎症细胞因子。这个项目 在最近的实验中，我们的意外发现引起了人们的注意。解剖分子机制 肝肿瘤发生具有诱导基因靶向系统MX1-CRE，我们确定了强大的肿瘤抑制作用 聚激素多胞胞二酸（Polyic）的作用，一种影响IFN表达的合成dsRNA。这些数据 IFN信号不仅挑战肝肿瘤发生中IL1A-IL6细胞因子回路的广为已知的理论，而且还挑战 还为HCC免疫疗法开辟了新的策略。但是，初步数据还表明注射 多元素进入老年小鼠，触发了急剧不同的免疫回报，实际上汇总了HCC的进展 如果在晚期肿瘤阶段给予。那我们假设IFN和其他相关炎症细胞因子具有 双向或悖论在HCC发育中的作用，具体取决于年龄和肿瘤阶段。测试这个 假设，我们将广泛询问IFN信号在单细胞上NASH-HCC模型中的作用 解决。我们还将进一步开发和优化数学模型和Ti（肿瘤指数）计算 定量测量致瘤信号强度，肿瘤阶段和预后的系统，还评估 各种操纵或治疗策略的肿瘤抑制作用。值得注意的是，也显示了初步数据 肝脏中多种元素对PD-L1表达的稳健诱导，这促使我们测试了多个聚合物的组合 和PD-L1/PD-1桶，用于治疗年轻小鼠肝癌的治疗。我们将广泛调查 先天性和适应性免疫功能的协调激活如何有效抑制主要和 肝脏转移性肿瘤进展。最后，我们将利用新建立的小鼠肿瘤 模型，系统地寻找肝脏特异性因素和对免疫疗法的抗性机制。全部 在这个雄心勃勃的项目中提出的实验只能与Shadel，Adams和 Kaech具有完整的专业知识和核心。