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

项目摘要 肝细胞癌（HCC）占所有肝癌的90%，具有18%的令人沮丧的5年存活率， 在过去的20年中，HCC的发病率增加了40%以上。HCC通常发生在以下患者中： 慢性肝病，包括酒精性肝病（ALD）、B或C型肝炎感染和非酒精性脂肪肝。 肝脏疾病ALD是HCC的主要原因之一，并且从慢性肝损伤发展为纤维化， 最后是肝硬化和肝癌。CD 8 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。然而，纤维化损害CD 8 T细胞抗原识别， 在ALD诱导的HCC肿瘤中发现很少的CD 8 T细胞，这表明慢性肝损伤损害了 免疫监视和导致HCC的发展。然而，酒精利用的机制- 损伤的肝细胞抑制免疫监视和促进HCC进展是不明确的。 自分泌运动因子（ATX）是一种分泌型酶，其结合细胞上的特异性受体并产生生物活性物质， 磷脂、溶血磷脂酸（LPA）。ATX血清水平与肝纤维化、肝脏分期正相关 疾病和HCC的发展，独立于疾病的初始诱导物。在肝脏内，ATX是 ATX由肝细胞组成性表达，并且过量的ATX产生有助于肝纤维化。醇 诱导DNA损伤，这是已知的增加ATX表达;一个过程可能加剧， 肝细胞慢性酒精消耗。LPA是6 G蛋白偶联受体的同源配体 由多种细胞类型表达。肝脏容纳免疫细胞和肝细胞，非常接近ATX- 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CD 8 T细胞功能并促进疾病。我们已经表明 通过CD 8 T细胞上的LPAR 5的LPA信号传导通过抑制CD 8 T细胞杀伤来阻止抗肿瘤免疫 能力然而，在肝脏内，许多细胞类型表达LPAR并具有抑制T细胞功能的能力， 我们推测肝细胞增加的LPA信号传导可能损害CD 8 T细胞功能。我们建议 慢性饮酒诱导的肝ATX表达持续增加促进了肝细胞的凋亡， 免疫抑制环境损害CD 8 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 在肿瘤发展之前或之后肝损伤后的ATX/LPA信号传导预防或治疗HCC 肿瘤进展。成功完成这一提案将扩大我们的理解如何ALD诱导 ATX表达促进CD 8 T细胞功能的肝脏免疫抑制，并将确立ATX治疗的任何益处。 使用ATX和/或特异性LPAR抑制剂治疗HCC。

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.