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

已有研究表明，肿瘤已发展出多种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的生长，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是最近发现的一种细胞群，已被证明在患有肝癌的小鼠和人类中都能削弱肿瘤特异性免疫反应。肝癌大多数发生在患有肝炎等潜在慢性肝病的患者中。慢性感染可导致MDSCs频率增加。我们正在研究MDSCs在小鼠肝炎中的特殊作用。髓系抑制细胞(MDSC)是一种异质性的未成熟髓系细胞，在患者和小鼠的慢性炎症和肿瘤发展过程中聚集在血液、肝脏、脾和肿瘤中。急性肝炎的特点是肝脏中炎性细胞的快速渗透和该器官酶活性的增加，这可能导致肝纤维化和肝硬化。我们对急性肝炎时肝MDSC的生物学特性进行了研究。出乎意料的是，积聚在皮下肿瘤小鼠肝脏中的肝脏MDSC未能抑制ConA注射后的炎症反应，相反，它导致了急性肝损伤的加剧。表型、遗传学和功能研究表明，在ConA注射后3小时，肝脏MDSC迅速从抑制表型转变为促炎表型。ConA治疗后，小鼠的促炎细胞因子、共刺激分子CD80、CD86和CD40的表达增加，抑制功能丧失。这些变化是CD40依赖的，在CD40-/-MDSC中没有发现。有趣的是，CD40结扎体外培养的人骨髓间充质干细胞可下调精氨酸酶I的表达和抑制功能。最后，阻断肝MDSC中ROS的产生可改善肝细胞损伤，提示MDSC介导的毒性是ROS依赖的。我们认为，这些发现反映了MDSC的可塑性如何被调节以促进炎症，为针对癌症患者的天然抑制细胞的治疗开辟了一条新的途径。

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.