Chronic alcohol consumption results in elevated Autotaxin levels that suppress anti-tumor immunity

长期饮酒会导致自分泌运动因子水平升高，从而抑制抗肿瘤免疫力

• 批准号: 10595090
• 负责人: Raul Martin Torres
• 金额: $ 17.87万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595090
• 关键词: Alcohol consumption; Alcoholic Liver Diseases; Alcoholic liver damage; Alcohols; Antigens; Automobile Driving; Binding; CD8-Positive T-Lymphocytes; Cancerous; Cell physiology; Cell surface; Cells; Chronic; Cirrhosis; Clinical; DNA Damage; Data; Development; Discontinuous Capillary; Disease; Environment; Enzymes; Etiology; Fibrosis; Funding; G-Protein-Coupled Receptors; GPR6 gene; Health; Hepatic; Hepatitis B; Hepatitis C; Hepatocyte; Immune; Immune system; Immunity; Immunologic Surveillance; Immunosuppression; Impairment; Incidence; Infection; Integrins; Ligands; Liver; Liver Fibrosis; Liver diseases; Lysophosphatidic Acid Receptors; Lysophosphatidylcholines; Malignant - descriptor; Malignant Epithelial Cell; Malignant neoplasm of liver; Mediator; Mission; National Institute on Alcohol Abuse and Alcoholism; Occupations; Patient-Focused Outcomes; Patients; Phospholipase D; Phospholipids; Pre-Clinical Model; Preventive treatment; Primary carcinoma of the liver cells; Process; Production; Role; Secure; Serum; Signal Induction; Signal Pathway; Signal Transduction; Structure; Survival Rate; T-Cell Receptor; T-Lymphocyte; Therapeutic; Treatment Protocols; Tumor Immunity; Tumor Promotion; United States National Institutes of Health; adaptive immune response; alcohol misuse; cancer cell; cell injury; cell killing; cell type; chronic alcohol ingestion; chronic liver disease; curative treatments; cytokine; cytotoxicity; experimental study; immune clearance; immune system function; improved; in vivo; inhibitor; liver injury; lysophosphatidic acid; mouse model; non-alcoholic fatty liver disease; prevent; receptor; tumor; tumor growth; tumor progression

PROJECT SUMMARY Hepatocellular carcinoma (HCC) comprises 90% of all liver cancers, has a dismal 5-year survival rate of 18%, and the incidence of HCC has increased over 40% in the last 20 years. HCC typically develops in patients with chronic liver disease including alcohol liver disease (ALD), Hepatitis B or C infection, and nonalcoholic fatty liver disease. ALD is one of the leading causes of HCC and progresses from chronic hepatic insult to fibrosis, cirrhosis and finally HCC. Immunosurveillance by CD8 T cells clears damaged, malignant, or infected hepatocytes providing critical anti-tumor immunity. However, fibrosis impairs CD8 T cell antigen recognition and few CD8 T cells are found in ALD-induced HCC tumors, suggesting that chronic hepatic insult impairs immunosurveillance and resulting in the development of HCC. Yet, the mechanisms exploited by alcohol- damaged hepatocytes to suppress immunosurveillance and promote HCC progression are ill-defined. Autotaxin (ATX) is a secreted enzyme that binds to specific receptors on cells and produces a bioactive phospholipid, lysophosphatidic acid (LPA). ATX serum levels positively correlate with fibrosis, stage of liver disease, and development of HCC, independent of the initial inducer of disease. Within the liver, ATX is constitutively expressed by hepatocytes, and excessive ATX production contributes to liver fibrosis. Alcohol induces DNA damage, which is known to increase ATX expression; a process likely exacerbated in hepatocytes by chronic alcohol consumption. LPA, is the cognate ligand for 6 G protein-coupled receptors expressed by a variety of cell types. The liver houses both immune and hepatic cells in close proximity to ATX- producing hepatocytes which signal via LPA receptors (LPARs). Many immunosuppressive mechanisms are exploited in malignant environments to suppress CD8 T cell function and promote disease. We have shown that LPA signaling via LPAR5 on CD8 T cells prevents anti-tumor immunity via suppressing CD8 T cell killing ability. Yet, within the liver, many cell types express LPAR and possess ability to suppress T cell function and we postulate increased LPA signaling by hepatic cells may impair CD8 T cell function. We propose that persistently increased liver ATX expression induced by chronic alcohol consumption promotes an immunosuppressive environment that impairs CD8 T cell function leading to the development of HCC. Experiments described in this proposal will determine if and how the ATX/LPA axis is exploited in chronic ALD resulting in in the hepatic microenvironment suppressing T cell immunity. Further, we will assess if inhibition of ATX/LPA signaling following hepatic damage before or after tumor development either prevents or treats HCC tumor progression. Successful completion of this proposal will expand our understanding of how ALD-induced ATX expression promotes hepatic immunosuppression of CD8 T cell function and will establish any benefit of using ATX and/or specific LPAR inhibitors in the treatment of HCC.

项目摘要 肝细胞癌（HCC）占所有肝癌的90％，5年生存率为18％， 在过去的20年中，HCC的发病率增加了40％以上。 HCC通常在患有 慢性肝病，包括酒精肝病（ALD），乙型肝炎或C感染和非酒精脂肪 肝病。 ALD是HCC的主要原因之一，从慢性肝侮辱到纤维化， 肝硬化和最终HCC。 CD8 T细胞的免疫监视清除受损，恶性或感染 提供关键的抗肿瘤免疫力的肝细胞。但是，纤维化会损害CD8 T细胞抗原识别 在ALD诱导的HCC肿瘤中发现CD8 T细胞很少，这表明慢性肝损伤会损害 免疫监护和导致HCC的发展。然而，酒精利用的机制 受损的肝细胞抑制免疫监视和促进HCC进展的定义不明确。 自动肝素（ATX）是一种分泌的酶，与细胞上的特定受体结合并产生生物活性 磷脂，溶物磷脂酸（LPA）。 ATX血清水平与纤维化呈正相关，肝脏的阶段 疾病和HCC的发展，与疾病的初始诱导剂无关。在肝内，ATX是 由肝细胞组成性表达，过多的ATX产生有助于肝纤维化。酒精 诱导DNA损伤，已知会增加ATX表达；一个可能加剧的过程 长期饮酒的肝细胞。 LPA是6 g蛋白偶联受体的同源配体 由多种细胞类型表示。肝脏在靠近ATX- 产生通过LPA受体（LPARS）发出信号的肝细胞。许多免疫抑制机制是 在恶性环境中开发以抑制CD8 T细胞功能并促进疾病。我们已经显示了 通过CD8 T细胞上的LPAR5信号传导通过抑制CD8 T细胞杀伤来防止抗肿瘤免疫 能力。然而，在肝脏中，许多细胞类型表达LPAR并具有抑制T细胞功能的能力， 我们假定肝细胞增加的LPA信号传导可能会损害CD8 T细胞功能。我们提出了这一点 持续增加的肝脏饮酒诱导的肝ATX表达会促进 免疫抑制环境会损害CD8 T细胞功能，从而导致HCC的发展。 该提案中描述的实验将确定在慢性ALD中如何利用ATX/LPA轴是否以及如何利用ATX/LPA轴 导致肝微环境抑制T细胞免疫。此外，我们将评估抑制 肿瘤发育前或之后，ATX/LPA信号传导可防止或治疗HCC 肿瘤进展。该提案的成功完成将扩大我们对ALD诱导的方式的理解 ATX表达促进CD8 T细胞功能的肝免疫抑制，并将建立任何好处 使用ATX和/或特定的LPAR抑制剂治疗HCC。