Sorting Out Pandora's Box: Discerning the Dynamic Roles of Liver Microenvironment in Oncolytic Virus Therapy for Hepatocellular Carcinoma

Abstract

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.

Keywords: hepatocellular carcinoma; immunotherapy; liver microenvironment; oncolytic virus; viral engineering.

Figure 1

Features of the hepatic microenvironment which challenge the fate of OVs. The innate immune response in the liver consists of scavenger Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs) and resident NK and NKT cells, which are efficient at clearing invading oncolytic viruses from the liver. KCs and NK/NKT cells secrete a variety of antiviral cytokines in response to infection, which substantially limit the replication of OVs in hepatocellular carcinoma (HCC). Material from dying virus-infected cells mediates cross-priming of T-cell responses by dendritic cells (DCs) and thereby induces an adaptive immune response against the virus. Hepatic stellate cells, which reside in the space of Disse, become activated during tumorigenesis causing them to migrate and secrete copious amounts of extracellular matrix (ECM) components, which hinder intratumoral cell-to-cell spread of OVs. Infected hepatocytes enter an anti-viral state and secrete type I interferons (IFNs), which protect the neighboring liver cells from infection and could also infer protection to HCC cells that are partially sensitive to IFN.