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.

项目摘要 肝癌在发病率和死亡率方面分别排名第五和第三， 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，肝炎B，C）或损伤驱动的慢性炎症（例如，肝硬化 过量饮酒或肥胖引起的脂肪性肝炎）。虽然HBV和HCV的发病率 在下降的同时，肥胖症的流行导致了HCC新发病例的增加， 包括美国在内的发达国家。因此，鉴定HCC的靶向介质代表了重要的 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起免疫调节作用。IL27R 信号传导表面上通过抑制促炎症因子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IL 27可能具有类似的功能， 炎症和阻止HCC发展。然而，令人惊讶的是，我们发现，消除IL 27 R 在两种体内肝癌小鼠模型中，信号传导抑制肿瘤的发展， 先天性和适应性细胞毒性免疫细胞的积累和激活增加，表明一种新的，亲- 这种抗炎细胞因子的致瘤作用。 在这里，我们打算研究IL 27 R信号如何抑制 使用与人肝癌高度相关的MUP-uPA小鼠模型组合的抗癌细胞毒性免疫反应 通过IL 27 R的细胞类型特异性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，我们将测试其功效并识别细胞和 单独或与其它免疫疗法组合的IL 27信号传导阻断的分子机制， 作为HCC的新治疗途径。 总的来说，这项研究将揭示IL 27 R信号在HCC发展中的作用， 确定其封锁的有利机制。这项工作具有很强的翻译潜力与游戏- 改变HCC的影响。