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

项目总结 肝癌的发病率排名第五，死亡率排名第三，估计新增病例超过70万 每年在全球范围内。肝细胞癌是最常见的一种起源于 由于病毒感染(例如，乙肝、丙型肝炎)或损伤导致的慢性炎症(例如，过度的肝硬变) 饮酒或肥胖引起的脂肪性肝炎)。尽管乙肝和丙型肝炎的发病率在上升 这一下降，肥胖的流行导致了发达国家肝癌新发病例的增加 包括美国在内的国家。因此，识别肝脏炎症和肝细胞癌的靶向介质代表着一种 重要的未得到满足的医疗需求。 白介素27是一种新近发现的细胞因子，在感染和感染中具有免疫调节作用。 自身免疫力。IL-27R信号通路减轻小鼠动脉粥样硬化模型和实验性炎症反应 脑脊髓炎(EAE)，表面上是通过抑制促炎免疫反应。这些发现导致了 美国推测，IL-27可能具有类似的功能，以限制肝脏炎症和阻止肝癌的发展。 然而，令人惊讶的是，我们发现消除IL-27R信号会减少肿瘤的发展。 小鼠肝细胞癌模型，提示这种抗炎作用在肝细胞癌中具有新的促肿瘤作用 细胞因子。 在此，我们拟探讨IL-27R信号通路促进糖尿病发生的机制(S)。 目的：探讨阻断IL-27作为治疗肝癌新途径的疗效。要做到这一点， 我们将使用IL-27缺陷(Il27ra-/-)小鼠在已确定的致癌物(二乙基亚硝胺，或DEN)诱导下 肝癌的模型。我们假设IL-27R信号改变了促肿瘤和抗肿瘤之间的平衡 肝细胞癌中的免疫反应，并将确定IL-27介导这些效应的细胞机制。我们 将阐明IL-27R信号如何在肝癌发展过程中调节免疫细胞的激活和功能 集成了一系列遗传建模、组织学、尖端成像和分子生物学方法。 最后，我们将测试IL-27阻断的疗效，无论是单独还是与其他免疫疗法联合使用， 作为治疗肝细胞癌的新途径。 总体而言，这项拟议的研究将揭示IL-27R信号在肝细胞癌发生中的作用。这部作品 具有强大的翻译潜力，对HCC产生了改变游戏规则的分支。

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.