Tumor Restrictions to Oncolytic Virus

Abstract

Oncolytic virotherapy has advanced since the days of its conception but therapeutic efficacy in the clinics does not seem to reach the same level as in animal models. One reason is premature oncolytic virus clearance in humans, which is a reasonable assumption considering the immune-stimulating nature of the oncolytic agents. However, several studies are beginning to reveal layers of restriction to oncolytic virotherapy that are present before an adaptive neutralizing immune response. Some of these barriers are present constitutively halting infection before it even begins, whereas others are raised by minute cues triggered by virus infection. Indeed, we and others have noticed that delivering viruses to tumors may not be the biggest obstacle to successful therapy, but instead the physical make-up of the tumor and its capacity to mount antiviral defenses seem to be the most important efficacy determinants. In this review, we summarize the constitutive and innate barriers to oncolytic virotherapy and discuss strategies to overcome them.

Keywords: antiviral defenses; extracellular matrix; interferon; oncolytic virus; tight junctions; tumor stroma.

Figure 1

Tumor stroma blocks virus spread within tumors. A representative section of human A2058 melanoma xenografts stained with polyclonal Semliki Forest virus (SFV) antibodies (in brown) shows that even following intratumoral injection, virus infection is delimited by non-permissive stromal cells and the extracellular matrix (collectively called stroma). We have studied these barriers in detail previously [25].

Figure 2

Schematic illustration of some physical barriers to oncolytic viruses and ways to overcome them. Tumor nests are often surrounded by extracellular matrix (ECM), which prevents viruses from reaching the tumor cells (see also Figure 1). Another problem is that tight junctions hide virus receptors and limit diffusion of viruses into the tumor tissue. Newly developed tight junction openers [40,47,48] may facilitate virus infection by exposing the hidden receptors, and virus-encoded proteases may degrade the stromal shield surrounding tumor nests [26].

Figure 3

Restricted infection by oncolytic virus in the absence of physical barriers. Intracranial syngeneic Balb/c mouse DBT gliomas (T) were injected into the same stereotactic coordinates with high-dose oncolytic Semliki Forest virus (SFV) vector VA7. Brains were sampled and stained for SFV antigens 24 h post virus injection (in brown), showing that SFV predominantly infects normal brain parenchymal cells rather than glioma cells. DBT tumors are homogeneous and void of thick extracellular matrix deposits, as seen in Figure 1, arguing that tumor cells resist virus infection by other intracellular means [60].