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

项目总结 肝癌的发病率排名第五，死亡率排名第三，估计新增肝癌人数超过70万人 全世界每年都有病例。肝细胞癌(HCC)是最常见的一种肝癌 起源于病毒感染(例如，乙肝、丙型肝炎)或损伤导致的慢性炎症(例如， 过量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 都在下降，肥胖症的流行导致#年肝癌新病例的增加 包括美国在内的发达国家。因此，确定肝细胞癌的靶向介质是一个重要的 未得到满足的医疗需求。 白介素27是一种在感染和自身免疫中发挥免疫调节作用的细胞因子。IL27R 信号表面上通过抑制前信号转导途径减少感染和炎症模型中的炎症反应 炎性免疫反应。这些发现使我们推测IL27可能具有类似的限制肝脏的功能 炎症和阻止肝癌的发展。然而，令人惊讶的是，我们发现消除IL27R 信号转导抑制两种体内肝细胞癌小鼠模型的肿瘤发展 天然和适应性细胞毒性免疫细胞的积累和激活增加，提示一种新的、有利于 这种抗炎细胞因子的致癌作用。 在这里，我们建议研究IL27R信号如何抑制的细胞和分子机制 联合应用高度相关的人肝癌MUP-uPA小鼠模型抗肿瘤细胞毒免疫应答 通过特定细胞类型的IL27R消融和尖端转录学、组织学、 免疫学和分子生物学分析。最后，我们将测试疗效并鉴定细胞和 单独或与其他免疫疗法联合阻断IL27信号的分子机制 作为治疗肝细胞癌的新途径。 总体而言，拟议的研究将揭示IL27R信号在肝癌发生和发展中的作用。 确定其封锁的有利机制。这部作品对游戏有很强的翻译潜力- 改变肝细胞癌的后果。

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.