The role of IL-27 cytokine in hepatocellular carcinoma (HCC) development

IL-27细胞因子在肝细胞癌（HCC）发展中的作用

• 批准号: 9282396
• 负责人: Ekaterina Koltsova
• 金额: $ 19.9万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282396
• 关键词: Address; Alcohols; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Aspirin; Atherosclerosis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; Biological Testing; Biology; Blocking Antibodies; Carcinogens; Cell Count; Cell Proliferation; Cells; Cessation of life; Chronic; Cirrhosis; Data; Developed Countries; Developing Countries; Development; Diethylnitrosamine; Disease; Encephalomyelitis; Ensure; Epidemic; Equilibrium; Event; Fatty Liver; Frequencies; Genetic; Genetic Models; Healthcare; Heavy Drinking; Hepatitis B; Hepatitis B Incidence; Hepatitis C Incidence; Hepatocyte; Histologic; IL27RA gene; Image; Immune; Immune Cell Activation; Immune response; Immunotherapeutic agent; Immunotherapy; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-12; Interleukin-6; Interleukins; Liver; Liver diseases; LoxP-flanked allele; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Medical; Methods; Modality; Modeling; Modernization; Molecular; Mus; Obesity; Outcome Study; PDCD1LG1 gene; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase I/II Trial; Physiological; Population; Positioning Attribute; Preventive; Primary carcinoma of the liver cells; Receptor Signaling; Recruitment Activity; Recurrence; Refractory; Regulatory T-Lymphocyte; Research; Risk; Role; Scheme; Signal Transduction; Steatohepatitis; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxin; Tumorigenicity; Virus; Virus Diseases; Work; adaptive immune response; base; biochemical tools; cancer immunotherapy; cellular targeting; cytokine; efficacy testing; experience; experimental study; immunoregulation; in vivo; inflammatory milieu; liver inflammation; liver injury; member; mortality; mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; pre-clinical trial; receptor; therapeutic evaluation; tumor; 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 is 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 liver inflammation and HCC represents an important unmet medical need. Interleukin (IL)-27 is a recently discovered cytokine with immunomodulatory roles in infection and autoimmunity. IL-27R signaling reduces inflammation in murine models of atherosclerosis and experimental encephalomyelitis (EAE), ostensibly by suppressing a pro-inflammatory immune response. These findings led us to speculate that IL-27 might function similarly to limit liver inflammation and halt HCC development. Surprisingly, however, we have discovered that eliminating IL-27R signaling decreases tumor development in a mouse model of HCC, suggesting a new, pro-tumorigenic role in HCC for this otherwise anti-inflammatory cytokine. Here we propose to investigate the mechanism(s) by which IL-27R signaling promotes development of HCC and to test the efficacy of IL-27 blockade as a new therapeutic approach for this malignancy. To do so, we will use IL-27-deficient (Il27ra-/-) mice in an established carcinogen (diethylnitrosamine, or DEN)-induced model of liver cancer. We hypothesize that IL-27R signaling alters the balance between pro- and anti-tumor immune responses in HCC, and will define the cellular mechanisms by which IL-27 mediates these effects. We will elucidate how IL-27R signaling regulates immune cell activation and function during HCC development by integrating an array of genetic modeling, histological, cutting-edge imaging and molecular biological methods. Finally, we will test the efficacy of IL-27 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 IL-27R signaling in HCC development. This work has strong translational potential with game-changing ramifications for HCC.

项目摘要 肝癌在发病率和死亡率方面分别排名第五和第三，估计新发病例超过70万例。 每年在世界各地。肝细胞癌（HCC）是最常见的肝癌形式， 来自病毒感染（例如，肝炎B，C）或损伤驱动的慢性炎症（例如，肝硬变 酒精消耗或肥胖引起的脂肪性肝炎）。虽然HBV和HCV的发病率在 在这种下降的同时，肥胖症的流行导致了发达国家HCC新发病例数量的增加。 包括美国在内的国家。因此，鉴定肝脏炎症和HCC的靶向介质代表了一种新的治疗方法。 重要的未满足的医疗需求。 白细胞介素（IL）-27是最近发现的在感染中具有免疫调节作用的细胞因子， 自身免疫IL-27 R信号转导减少了动脉粥样硬化小鼠模型和实验动物中的炎症 脑脊髓炎（EAE），表面上通过抑制促炎性免疫反应。基于这些发现得出 我们推测IL-27可能具有类似的功能，以限制肝脏炎症和阻止HCC的发展。 然而，令人惊讶的是，我们已经发现，消除IL-27 R信号转导减少了肿瘤的发展， 小鼠肝癌模型，表明这种抗炎药在肝癌中具有新的促肿瘤作用 细胞因子 在这里，我们打算研究IL-27 R信号转导促进肿瘤发生的机制。 并测试IL-27阻断作为这种恶性肿瘤的新治疗方法的功效。要执行此操作， 我们将使用IL-27缺陷型（IL-27 ra-/-）小鼠在一个已建立的致癌物（二乙基亚硝胺，或DEN）诱导的 肝癌模型。我们假设IL-27 R信号转导改变了促肿瘤和抗肿瘤之间的平衡。 研究表明，IL-27可以诱导HCC中的免疫应答，并将确定IL-27介导这些作用的细胞机制。我们 将阐明IL-27 R信号如何调节免疫细胞的激活和功能，在肝癌的发展， 整合了一系列遗传建模、组织学、尖端成像和分子生物学方法。 最后，我们将测试IL-27阻断剂单独或与其他免疫疗法组合的功效， 作为HCC的新治疗途径。 总的来说，拟议的研究将揭示IL-27 R信号在HCC发展中的作用。这项工作 具有很强的转化潜力，对HCC具有改变游戏规则的影响。