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

项目总结 肝细胞癌占所有肝癌的90%，5年生存率低达18%， 在过去的20年里，肝癌的发病率增加了40%以上。肝细胞癌通常发生在患有 慢性肝病，包括酒精性肝病(ALD)、乙型或丙型肝炎感染和非酒精性脂肪 肝病。ALD是肝细胞癌的主要病因之一，从慢性肝损害发展为纤维化， 肝硬变，最后是肝癌。CD8 T细胞的免疫监控可清除受损、恶性或感染 提供关键的抗肿瘤免疫的肝细胞。然而，纤维化损害了CD8 T细胞抗原识别 ALD诱导的肝细胞癌中CD8T细胞很少，提示慢性肝损伤损害 免疫监视和导致肝细胞癌的发展。然而，酒精利用的机制- 受损的肝细胞抑制免疫监视和促进肝细胞癌进展的定义并不明确。 自体趋化蛋白(ATX)是一种分泌酶，能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)。血清ATX水平与肝纤维化、肝组织分期呈正相关 疾病和肝细胞癌的发展，与最初的疾病诱因无关。在肝脏内，ATX是 由肝细胞组成性表达，ATX的过度产生导致肝纤维化。酒精 诱导DNA损伤，已知这会增加ATX的表达；这一过程可能在 慢性饮酒引起的肝细胞损伤。LPA，是6G蛋白偶联受体的同源配体 由多种细胞类型表达。肝脏内有免疫细胞和肝细胞，与ATX密切相关。 产生肝细胞，通过LPA受体(LPAR)传递信号。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 CD8T细胞上LPAR5介导的LPA信号通过抑制CD8T细胞杀伤而抑制抗肿瘤免疫 才能。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 我们推测肝细胞LPA信号的增加可能损害CD8T细胞的功能。我们建议 慢性饮酒诱导的肝脏ATX表达持续增加促进 免疫抑制环境损害CD8T细胞功能，导致肝细胞癌的发生。 这项建议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信号转导可预防或治疗肝癌 肿瘤进展。这项提案的成功完成将扩大我们对ALD是如何导致 ATX的表达促进了CD8 T细胞功能的免疫抑制，并将建立任何有益于 使用ATX和/或特异性LPAR抑制剂治疗肝细胞癌。

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.