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: 10698110
• 负责人: Gen-Sheng Feng
• 金额: $ 40.84万
• 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/10698110
• 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; Disparity; Double-Stranded RNA; Endothelial Cells; Epigenetic Process; Etiology; Excision; Gene Targeting; Goals; Hepatic; Hepatic Mass; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocarcinogenesis; Hepatocyte; IL6 gene; Immune; Immune checkpoint inhibitor; Immune response; Immunologics; Immunotherapeutic agent; Immunotherapy; 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; 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 Promotion; Tumor Suppressor Proteins; Tumor stage; adaptive immunity; age related; aged; aging population; anti-PD-L1; cell type; chronic liver disease; comparative; cytokine; design; experimental study; high risk; immune function; indexing; innate immune function; insight; interdisciplinary approach; liver cancer model; liver cancer prevention; liver function; mathematical model; mitochondrial dysfunction; mouse model; non-alcoholic fatty liver disease; novel; older patient; premalignant; programmed cell death ligand 1; regenerative; resistance mechanism; response; restoration; theories; treatment strategy; tumor; tumor initiation; 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），是目前最致命的恶性疾病之一。 衰老是肝癌发生的一个高风险因素，尽管其潜在机制尚不清楚。 肝脏老化的特点是免疫抑制微环境的逐渐发展， 慢性干扰素 (IFN) 信号传导、代谢变化以及先天性和适应性免疫的改变所致。 因此，肝脏肿瘤对免疫治疗的反应较差。项目 4 的目标是阐明 IFN 的作用。 和其他炎症细胞因子在肝脏免疫景观的衰老相关变化中的作用。 是由我们在最近的实验中剖析分子机制时的意外发现所促成的。 通过诱导基因靶向系统 Mx1-cre 来研究肝脏肿瘤的发生，我们发现了一种强大的肿瘤抑制作用 聚肌苷-聚胞苷酸 (polyIC) 的作用，这是一种诱导 IFN 表达的合成 dsRNA。 IFN 信号传导不仅挑战了众所周知的 IL1a-IL6 细胞因子回路在肝脏肿瘤发生中的理论，而且 也为HCC免疫治疗开辟了新策略，不过，初步数据也显示，注射。 老年小鼠体内的多聚IC引发了截然不同的免疫反应，实际上加剧了肝癌的进展 如果在肿瘤晚期给予，我们就发现干扰素和其他相关的炎症细胞因子具有作用。 HCC 发展中的双向或矛盾作用，取决于年龄和肿瘤阶段。 假设，我们将广泛探讨单细胞 NASH-HCC 模型中 IFN 信号传导的作用 我们还将进一步开发和优化数学模型和 TI（致瘤指数）计算。 系统定量测量致瘤信号强度、肿瘤阶段和预后，并评估 值得注意的是，初步数据还显示了各种操作或治疗策略的肿瘤抑制作用。 PolyIC 在肝脏中强烈诱导 PD-L1 表达，这促使我们测试 PolyIC 的组合 以及PD-L1/PD-1阻断治疗年轻和年老小鼠肝癌的效果我们将进行广泛的研究。 先天性和适应性免疫功能的协调激活如何有效抑制原发性和适应性免疫 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免疫治疗耐药机制。 这个雄心勃勃的项目中拟议的实验只能与 Shadel、Adams 和 Kaech 拥有互补的专业知识和核心。