Sorting Out Pandora's Box: Discerning the Dynamic Roles of Liver Microenvironment in Oncolytic Virus Therapy for Hepatocellular Carcinoma.
Sorting Out Pandora's Box: Discerning the Dynamic Roles of Liver Microenvironment in Oncolytic Virus Therapy for Hepatocellular Carcinoma.
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DOI：
10.3389/fonc.2014.00085
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发表时间：
2014
影响因子：
4.7
通讯作者：
Ebert O
中科院分区：
文献类型：
--
作者：
Altomonte J;Ebert O
溶瘤病毒疗法最近已进入肝细胞癌（HCC）的临床应用，HCC是一种治疗选择有限且预后不良的疾病。除了体内溶瘤病毒疗法的许多内在挑战之外，肝脏的复杂微环境也是一个挑战，这对病毒的成功递送和繁殖造成了独特的限制。正常肝环境的特征在于肝细胞和非实质细胞（包括枯否细胞、星状细胞和窦状内皮细胞）的复杂网络，其可以分泌抗病毒细胞因子，为非特异性摄取提供平台，并形成有效病毒传播的屏障。此外，自然杀伤细胞在肝脏中非常丰富，有助于对病毒的先天防御。当HCC发生在基础肝炎病毒感染和/或肝硬化的情况下时，情况进一步复杂化，这发生在超过90%的临床病例中。由于存在慢性炎症、组成性细胞因子表达、改变的肝血流和细胞外基质沉积，这些病症对溶瘤病毒（OV）治疗造成进一步抑制作用。此外，OVs可以调节肝脏微环境，导致病毒与宿主之间复杂的相互作用。免疫系统无疑在OV治疗的结果中起着重要作用，既作为病毒复制的抑制剂，又作为病毒介导的肿瘤细胞杀伤的有效机制。本文将讨论溶瘤病毒治疗HCC的特殊挑战，以及一些潜在的策略，调节免疫系统和协同肝脏微环境，以改善治疗效果。
Oncolytic viral therapies have recently found their way into clinical application for hepatocellular carcinoma (HCC), a disease with limited treatment options and poor prognosis. Adding to the many intrinsic challenges of in vivo oncolytic viral therapy, is the complex microenvironment of the liver, which imposes unique limitations to the successful delivery and propagation of the virus. The normal liver milieu is characterized by an intricate network of hepatocytes and non-parenchymal cells including Kupffer cells, stellate cells, and sinusoidal endothelial cells, which can secrete anti-viral cytokines, provide a platform for non-specific uptake, and form a barrier to efficient viral spread. In addition, natural killer cells are greatly enriched in the liver, contributing to the innate defense against viruses. The situation is further complicated when HCC arises in the setting of underlying hepatitis virus infection and/or hepatic cirrhosis, which occurs in more than 90% of clinical cases. These conditions pose further inhibitory effects on oncolytic virus (OV) therapy due to the presence of chronic inflammation, constitutive cytokine expression, altered hepatic blood flow, and extracellular matrix deposition. In addition, OVs can modulate the hepatic microenvironment, resulting in a complex interplay between virus and host. The immune system undoubtedly plays a substantial role in the outcome of OV therapy, both as an inhibitor of viral replication, and as a potent mechanism of virus-mediated tumor cell killing. This review will discuss the particular challenges of oncolytic viral therapy for HCC, as well as some potential strategies for modulating the immune system and synergizing with the hepatic microenvironment to improve therapeutic outcome.