Immune suppressor mechanism in a murine model of hepatitis and liver cancer

研究表明，肿瘤已经发展出许多逃避肿瘤特异性免疫反应的方法。这些机制最终不仅会促进肿瘤生长，而且会损害基于免疫的癌症治疗的效果。髓系来源的抑制细胞是最近发现的一种细胞群，在小鼠和肝癌患者中显示出损害肿瘤特异性免疫反应。肝癌发生在大多数有潜在慢性肝病（如肝炎）的患者中。慢性感染可导致MDSCs的频率增加。我们正在研究MDSCs在小鼠肝炎中的具体作用。髓源性抑制细胞（myeloid -derived suppressor cells， MDSC）是一种异质性的未成熟髓细胞群，在患者和小鼠的慢性炎症和肿瘤发展过程中积聚在血液、肝脏、脾脏和肿瘤中。急性肝炎的特点是炎症细胞在肝脏中快速浸润，肝脏酶活性增加，可导致肝纤维化和肝硬化。我们研究了肝脏MDSC在急性肝炎中的生物学作用。出乎意料的是，在皮下肿瘤小鼠的肝脏中积累的肝MDSC在注射Con A后不能抑制炎症反应，反而会加剧急性肝损伤。表型、遗传和功能研究表明，早在注射Con a后3小时，肝脏MDSC就会从抑制表型迅速转变为促炎亚群。在Con a治疗的小鼠中，发现促炎细胞因子、共刺激分子如CD80、CD86和CD40的表达增加，同时抑制功能丧失。这些变化是CD40依赖性的，在CD40-/- MDSC中没有发现。有趣的是，体外人MDSC的CD40连接导致精氨酸酶I表达和抑制功能下调。最后，阻断肝MDSC中ROS的产生可改善肝细胞损伤，这表明MDSC介导的毒性依赖于ROS。我们相信这些发现反映了MDSC可塑性如何被调节以促进炎症，为癌症患者的先天性抑制细胞治疗开辟了新的途径。

It has been shown that tumors have developed numerous ways to escape tumor specific immune responses. These mechanisms will ultimately not only enhance tumor growth, but also impair the effect of immune based therapies in cancer. Myeloid derived suppressor cells represent a recently identified cell population, which has been shown to impair tumor specific immune responses both in mice and human with liver cancer. Liver cancer occurs in the majority of cases in patients with an underlying chronic liver disease such as hepatitis. Chronic infections can lead to an increase in the frequency of MDSCs. We are investigating the specific role of MDSCs in the context of hepatitis in mice. Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells that accumulate in blood, liver, spleen and tumors upon chronic inflammation and tumor development in patients and mice. Acute hepatitis is characterized by a fast infiltration of inflammatory cells in the liver and increased enzymatic activity at this organ that could lead into liver fibrosis and cirrhosis. We have studied the biology of hepatic MDSC in acute hepatitis. Unexpectedly, hepatic MDSC, which accumulate in the liver of mice bearing subcutaneous tumors, failed to suppress inflammatory responses upon Con A injection, but instead were responsible for exacerbating acute liver damage. Phenotypic, genetic and functional studies demonstrated rapid changes of hepatic MDSC from a suppressor phenotype into a pro-inflammatory subset as early as 3 hours after Con A injection. An increase in the expression of pro-inflammatory cytokines, costimulatory molecules such as CD80, CD86 and CD40 along with a loss of suppressor function was noticed in mice upon Con A treatment. These changes were CD40-dependent and not found in CD40-/- MDSC. Interestingly, CD40 ligation of human MDSC in vitro resulted in down-regulation of arginase I expression and suppressor function. Finally, blockade of ROS production in hepatic MDSC ameliorated hepatocyte damage suggesting that MDSC mediated toxicity was ROS dependent. We believe that these findings reflect how MDSC plasticity can be modulated to promote inflammation, opening a new path for therapies targeting innate suppressive cells in cancer patients.