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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肝细胞癌 (HCC) 占所有肝癌的 90%，5 年生存率仅为 18%，近20年来，HCC的发病率增加了40%以上。 HCC 通常发生于以下患者：慢性肝病，包括酒精性肝病 (ALD)、乙型或丙型肝炎感染以及非酒精性脂肪肝肝脏疾病。 ALD 是 HCC 的主要原因之一，从慢性肝损伤进展为纤维化，肝硬化，最后是肝癌。 CD8 T 细胞的免疫监视清除受损、恶性或感染肝细胞提供关键的抗肿瘤免疫力。然而，纤维化会损害 CD8 T 细胞抗原识别在 ALD 诱导的 HCC 肿瘤中发现很少的 CD8 T 细胞，这表明慢性肝损伤会损害免疫监视并导致 HCC 的发展。然而，酒精利用的机制受损肝细胞抑制免疫监视和促进 HCC 进展的作用尚不明确。自分泌运动因子 (ATX) 是一种分泌酶，可与细胞上的特定受体结合并产生生物活性磷脂、溶血磷脂酸（LPA）。 ATX血清水平与纤维化、肝脏分期呈正相关疾病和 HCC 的发展，与疾病的初始诱导因素无关。在肝脏内，ATX 由肝细胞组成型表达，过量的 ATX 产生会导致肝纤维化。酒精诱导 DNA 损伤，已知这会增加 ATX 的表达；这一过程可能会加剧长期饮酒会损害肝细胞。 LPA，是 6 G 蛋白偶联受体的同源配体由多种细胞类型表达。肝脏中含有靠近 ATX 的免疫细胞和肝细胞产生通过 LPA 受体 (LPAR) 发出信号的肝细胞。许多免疫抑制机制是在恶性环境中被利用来抑制 CD8 T 细胞功能并促进疾病。我们已经展示了 CD8 T 细胞上 LPAR5 的 LPA 信号通过抑制 CD8 T 细胞杀伤来防止抗肿瘤免疫能力。然而，在肝脏内，许多细胞类型表达 LPAR 并具有抑制 T 细胞功能和我们假设肝细胞 LPA 信号传导增加可能会损害 CD8 T 细胞功能。我们建议长期饮酒诱导的肝脏 ATX 表达持续增加可促进免疫抑制环境损害 CD8 T 细胞功能，导致 HCC 的发展。本提案中描述的实验将确定 ATX/LPA 轴是否以及如何在慢性 ALD 中被利用导致肝脏微环境抑制T细胞免疫。此外，我们将评估是否抑制肿瘤发生前后肝损伤后的 ATX/LPA 信号传导可预防或治疗 HCC 肿瘤进展。该提案的成功完成将扩大我们对 ALD 如何诱导的理解 ATX 表达促进 CD8 T 细胞功能的肝脏免疫抑制，并将确定以下因素的任何益处：使用 ATX 和/或特定 LPAR 抑制剂治疗 HCC。