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Review
. 2022 Feb 12:24:663-682.
doi: 10.1016/j.omto.2022.02.004. eCollection 2022 Mar 17.

Infection of non-cancer cells: A barrier or support for oncolytic virotherapy?

Victor A Naumenko  1 , Aleksei A Stepanenko  1   2 , Anastasiia V Lipatova  3 , Daniil A Vishnevskiy  1 , Vladimir P Chekhonin  1   2
Affiliations
Review

Infection of non-cancer cells: A barrier or support for oncolytic virotherapy?

Victor A Naumenko et al. Mol Ther Oncolytics. .

Abstract

Oncolytic viruses are designed to specifically target cancer cells, sparing normal cells. Although numerous studies demonstrate the ability of oncolytic viruses to infect a wide range of non-tumor cells, the significance of this phenomenon for cancer virotherapy is poorly understood. To fill the gap, we summarize the data on infection of non-cancer targets by oncolytic viruses with a special focus on tumor microenvironment and secondary lymphoid tissues. The review aims to address two major questions: how do attenuated viruses manage to infect normal cells, and whether it is of importance for oncolytic virotherapy.

Keywords: cancer therapy; infection of non-cancer cells; oncolytic virus; secondary lymphoid tissues; tumor microenvironment.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Tumor microenvironment sensitizes endothelium for OV infection Upregulation of proangiogenic signaling in a growing tumor makes ECs vulnerable to OV infection via several mechanisms: (1) increased permeability of neovessels facilitates OV accumulation in the perivascular area; (2) actively proliferating ECs provide OVs with ribonucleotide reductase (RR), the enzyme essential for virus replication; and (3) vascular endothelial growth factor (VEGF) binding to VEGFR2 activates transcription repressor PRD1-BF1, which interferes with genes involved in type I interferon (IFN)-mediated antiviral signaling. Additionally, cancer cells and reprogrammed stromal cells create an immunosuppressive milieu favoring OV replication in the tumor microenvironment. In turn, EC infection may promote antitumor responses by (1) secreting proinflammatory cytokines; (2) recruiting/activating immune cells; (3) launching vascular shutdown; and (4) supporting OV spread in the tumor. TAMs, tumor-associated macrophages; CAF, cancer-associated fibroblast; MDSC, myeloid-derived suppressor cell.
Figure 2
Figure 2
Secondary lymphoid organs allow controlled OV replication (exemplified by spleen) Unique properties of MMMs determine their permissiveness to OVs: due to anatomical location, these cells accommodate high concentration of systemically injected OVs; (2) Usp18 upregulation blocks type I IFN-mediated response in MMMs. Transient viral replication in CD169+ cells is crucial for eliciting rapid antiviral responses by (1) secreting type I IFN and other cytokines; (2) recruiting inflammatory cells; (3) priming T and B cell responses; and (4) multiplying antigen for activation of neighboring dendritic cells. Moreover, MMMs can transfer cell-surface-associated infectious virions to B cells and DCs, contributing to the infection of these cells. Virus replication in DCs further increases type I IFN production in the lymphoid tissues and improves the efficiency of antigen presentation. Additionally, B cells may transfer OVs directly to follicular DCs, enabling boost response in immunized hosts.
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