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:
  • 金额:
    $ 17.87万
  • 依托单位:
  • 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

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.
项目总结

项目成果

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Raul Martin Torres其他文献

Raul Martin Torres的其他文献

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{{ truncateString('Raul Martin Torres', 18)}}的其他基金

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:
    10370159
  • 财政年份:
    2022
  • 资助金额:
    $ 17.87万
  • 项目类别:
Lysophosphatidic Acid Regulation of CD8 T cell activation and function
溶血磷脂酸对 CD8 T 细胞活化和功能的调节
  • 批准号:
    10116268
  • 财政年份:
    2020
  • 资助金额:
    $ 17.87万
  • 项目类别:
Lysophosphatidic Acid Regulation of CD8 T cell activation and function
溶血磷脂酸对 CD8 T 细胞活化和功能的调节
  • 批准号:
    10348723
  • 财政年份:
    2020
  • 资助金额:
    $ 17.87万
  • 项目类别:
Lysophosphatidic Acid Regulation of CD8 T cell activation and function
溶血磷脂酸对 CD8 T 细胞活化和功能的调节
  • 批准号:
    10574540
  • 财政年份:
    2020
  • 资助金额:
    $ 17.87万
  • 项目类别:
Humoral Immunity by Anergic B cells
无能 B 细胞的体液免疫
  • 批准号:
    10460932
  • 财政年份:
    2018
  • 资助金额:
    $ 17.87万
  • 项目类别:
Humoral Immunity by Anergic B cells
无能 B 细胞的体液免疫
  • 批准号:
    10199938
  • 财政年份:
    2018
  • 资助金额:
    $ 17.87万
  • 项目类别:
Marginal Zone B Cell Response to HIV
边缘区 B 细胞对 HIV 的反应
  • 批准号:
    7572911
  • 财政年份:
    2008
  • 资助金额:
    $ 17.87万
  • 项目类别:
Marginal Zone B Cell Response to HIV
边缘区 B 细胞对 HIV 的反应
  • 批准号:
    7462489
  • 财政年份:
    2008
  • 资助金额:
    $ 17.87万
  • 项目类别:
Chemokine response in B cell development and function
B 细胞发育和功能中的趋化因子反应
  • 批准号:
    6843138
  • 财政年份:
    2002
  • 资助金额:
    $ 17.87万
  • 项目类别:
Antigen and lysophospholipid receptor regulation of lymphocyte development and fu
抗原和溶血磷脂受体对淋巴细胞发育和功能的调节
  • 批准号:
    8846018
  • 财政年份:
    2002
  • 资助金额:
    $ 17.87万
  • 项目类别:

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揭示视黄酸受体β在酒精性肝病中的作用
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