IL-27R signaling as a negative regulator of innate and adaptive anti-cancer immunity in hepatocellular carcinoma

IL-27R 信号传导作为肝细胞癌先天性和适应性抗癌免疫的负调节因子

• 批准号: 10672351
• 负责人: Ekaterina Koltsova
• 金额: $ 65.06万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672351
• 关键词: Ablation; Anti-Inflammatory Agents; Antibodies; Autoimmune Diseases; Autoimmunity; Biological Assay; Biological Response Modifiers; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Cellular Metabolic Process; Chronic; Cirrhosis; Data; Developed Countries; Development; Disease; Family; Frequencies; Genetic; Genetic Transcription; Growth; Growth and Development function; Healthcare; Heavy Drinking; Hepatitis B; Hepatitis B Incidence; Hepatitis C Incidence; Hepatocyte; Histologic; Human; IL27RA gene; IL6 gene; Immune; Immune response; Immunologic Markers; Immunologics; Immunotherapy; In Vitro; Incidence; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Injury; Innate Immune Response; Interleukin-12; Interleukins; Intervention; Knock-out; Liver; Malignant neoplasm of liver; Mediating; Mediator; Medical; Modality; Modeling; Molecular; Molecular Biology; Mus; Natural Killer Cells; Obesity; Obesity Epidemic; Pathway interactions; Patients; Phenotype; Play; Preventive; Primary carcinoma of the liver cells; Proliferating; Regulation; Repression; Research; Risk Factors; Role; Scheme; Serum; Signal Transduction; Steatohepatitis; Survival Rate; T cell response; T-Cell Depletion; Testing; Therapeutic; Tumor Immunity; Up-Regulation; Virus Diseases; Work; adaptive immune response; anti-cancer; anti-tumor immune response; arm; cancer immunotherapy; cancer therapy; care burden; cell type; checkpoint therapy; cytokine; cytotoxic; cytotoxicity; efficacy testing; exhaustion; immune cell infiltrate; immunoregulation; in vivo; in vivo Model; liver cancer model; liver inflammation; liver injury; member; mortality; mouse model; nonalcoholic steatohepatitis; novel; novel therapeutics; pharmacologic; programmed cell death protein 1; receptor; response; targeted cancer therapy; therapeutic evaluation; transcriptomics; translational potential; tumor; tumor growth; tumorigenesis; tumorigenic

PROJECT SUMMARY Liver cancer ranks fifth in frequency and third in mortality, with estimated numbers of over 700,000 new cases every year worldwide. Hepatocellular carcinoma (HCC) is the most common form of liver cancer that originates from viral infection (e.g., hepatitis B, C) or injury-driven chronic inflammation (e.g., cirrhosis from excessive alcohol consumption or obesity-induced steatohepatitis) in the liver. Although HBV and HCV incidence are on the decline, the obesity epidemic has resulted in an increase in the number of new cases of HCC in developed countries including the US. Thus, identifying targetable mediators of HCC represents an important unmet medical need. Interleukin (IL)-27 is a cytokine that plays immunomodulatory roles in infection and autoimmunity. IL27R signaling reduces inflammation in infectious and inflammatory models ostensibly by suppressing a pro- inflammatory immune response. These findings led us to speculate that IL27 might function similarly to limit liver inflammation and halt HCC development. Surprisingly, however, we have discovered that eliminating IL27R signaling suppresses tumor development in two in vivo mouse models of HCC which was accompanied by the increased accumulation and activation of innate and adaptive cytotoxic immune cells, suggesting a new, pro- tumorigenic role for this otherwise anti-inflammatory cytokine. Here we propose to investigate cellular and molecular mechanisms of how IL27R signaling suppresses anti-cancer cytotoxic immune response using highly relevant to human HCC MUP-uPA mouse model combined with cell type specific ablation of IL27R and integrated array of cutting-edge transcriptomics, histological, immunological, and molecular biology analyses. Finally, we will test the efficacy and identify cellular and molecular mechanisms of IL27 signaling blockade either alone or in combination with other immunotherapies, as a new therapeutic avenue for HCC. Overall, the proposed research will uncover the role of IL27R signaling in HCC development and determine the beneficial mechanisms of its blockade. This work has strong translational potential with game- changing ramifications for HCC.

项目概要 肝癌的发病率排名第五，死亡率排名第三，估计新发病例数超过 70 万 全球每年都有病例。肝细胞癌 (HCC) 是最常见的肝癌形式， 源自病毒感染（例如乙型肝炎、丙型肝炎）或损伤引起的慢性炎症（例如肝硬化） 过量饮酒或肥胖引起的脂肪性肝炎）在肝脏中。尽管乙肝病毒和丙肝病毒的发病率 的下降，肥胖流行导致肝癌新发病例数增加 包括美国在内的发达国家。因此，识别 HCC 的靶向介质是一个重要的研究方向。 未满足的医疗需求。 白细胞介素 (IL)-27 是一种细胞因子，在感染和自身免疫中发挥免疫调节作用。 IL27R 表面上，信号传导通过抑制亲炎症来减少感染和炎症模型中的炎症 炎症免疫反应。这些发现使我们推测 IL27 可能具有类似的功能来限制肝脏 炎症并阻止 HCC 的发展。然而，令人惊讶的是，我们发现消除 IL27R 信号传导抑制两种体内 HCC 小鼠模型中的肿瘤发展，并伴有 先天性和适应性细胞毒性免疫细胞的积累和激活增加，这表明一种新的、亲 这种抗炎细胞因子的致瘤作用。 在这里，我们建议研究 IL27R 信号如何抑制的细胞和分子机制 使用与人类 HCC 高度相关的 MUP-uPA 小鼠模型联合抗癌细胞毒性免疫反应 具有细胞类型特异性的 IL27R 消融和尖端转录组学、组织学、 免疫学和分子生物学分析。最后，我们将测试功效并鉴定细胞和 单独或与其他免疫疗法联合阻断 IL27 信号传导的分子机制， 作为 HCC 的新治疗途径。 总体而言，拟议的研究将揭示 IL27R 信号在 HCC 发展和 确定其封锁的有益机制。这项工作具有很强的游戏转化潜力- 改变 HCC 的影响。