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

已经表明，肿瘤已经发展出许多方式来逃避肿瘤特异性免疫应答。这些机制最终不仅会促进肿瘤生长，还会削弱基于免疫的癌症治疗的效果。髓系来源的抑制细胞代表了最近鉴定的细胞群体，其已被证明在患有肝癌的小鼠和人中均损害肿瘤特异性免疫应答。肝癌发生在大多数情况下，患者有潜在的慢性肝病，如肝炎。慢性感染可导致MDSC频率增加。我们正在研究MDSC在小鼠肝炎背景下的具体作用。髓源性抑制细胞（MDSC）代表在患者和小鼠的慢性炎症和肿瘤发展后在血液、肝脏、脾脏和肿瘤中积累的不成熟髓细胞的异质群体。急性肝炎的特征是肝脏中炎症细胞的快速浸润和该器官酶活性的增加，这可能导致肝纤维化和肝硬化。我们研究了急性肝炎肝脏MDSC的生物学特性。出乎意料的是，在皮下肿瘤小鼠肝脏中积累的肝MDSC在Con A注射后未能抑制炎症反应，而是导致急性肝损伤加重。表型、遗传和功能研究表明，早在Con A注射后3小时，肝脏MDSC就从抑制表型迅速转变为促炎亚群。ConA处理后，小鼠中促炎细胞因子、共刺激分子如CD 80、CD 86和CD 40的表达增加，同时沿着抑制功能的丧失。这些变化是CD 40依赖性的，在CD 40-/- MDSC中未发现。有趣的是，在体外人MDSC的CD 40连接导致了抑制酶I表达和抑制功能的下调。最后，阻断肝MDSC中ROS的产生改善了肝细胞损伤，表明MDSC介导的毒性是ROS依赖性的。最终，这些发现为在荷瘤小鼠和潜在患者中成熟肝脏MDSC的新型CD 40介导方法提供了理论基础。

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. Ultimately these findings provide the rationale for novel, CD40 mediated, approaches to mature hepatic MDSC in tumor bearing mice and potentially in patients.