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

基本信息

批准号：
10504573
负责人：
Ekaterina Koltsova
金额：
$ 66.39万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10504573
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 Interleukin-12 Interleukins Intervention Knock-out Lead Liver Malignant neoplasm of liver Mediating Mediator of activation protein Medical Modality Modeling Molecular Molecular Biology Mus Natural Killer Cells Obesity Obesity Epidemic Pathway interactions Patients Pharmacology Phenotype Play Preventive Primary carcinoma of the liver cells Regulation 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 cell type checkpoint therapy cytokine cytotoxic cytotoxicity efficacy testing exhaustion immunoregulation in vivo in vivo Model liver cancer model liver inflammation liver injury member mortality mouse model nonalcoholic steatohepatitis novel novel therapeutics programmed cell death protein 1 receptor response targeted cancer therapy therapeutic evaluation transcriptomics translational potential tumor tumor growth tumorigenesis tumorigenic

项目摘要

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.

项目摘要肝癌的频率排名第五，死亡率排名第三，估计数量超过700,000 每年全球案件。肝细胞癌（HCC）是最常见的肝癌形式起源于病毒感染（例如，乙型肝炎，C）或受伤驱动的慢性炎症（例如，来自肝硬化肝脏中过量的饮酒或肥胖引起的脂肪性肝炎）。虽然HBV和HCV发病率肥胖流行正在下降，导致新的HCC案例数量增加包括美国在内的发达国家。因此，识别HCC的目标介质代表了一个重要的未满足的医疗需求。白介素（IL）-27是一种细胞因子，在感染和自身免疫性中起免疫调节作用。 IL27R 信号传导通过抑制促进性来减少表面上感染和炎症模型的炎症炎症免疫反应。这些发现导致我们推测IL27的起作用可能相似，以限制肝脏炎症和停止HCC的发育。但是，令人惊讶的是，我们发现消除IL27R 信号传导抑制了两个hcc的体内小鼠模型中的肿瘤发育，伴随着先天性和适应性细胞毒性免疫细胞的积累和激活增加，这表明是一种新的，这种原本抗炎细胞因子的致瘤作用。在这里，我们建议研究IL27R信号传导如何抑制IL27R的细胞和分子机制抗癌细胞毒性免疫反应使用与人HCC混乱小鼠模型高度相关的组合具有IL27R的细胞类型特异性消融和尖端转录组学的综合阵列，组织学免疫学和分子生物学分析。最后，我们将测试功效，并确定细胞和单独或与其他免疫疗法的IL27信号阻滞的分子机制，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开发中的作用和确定其封锁的有益机制。这项工作在游戏中具有强大的翻译潜力 - 更改HCC的后果。