Mesenchymal stem cell-released oncolytic virus: an innovative strategy for cancer treatment

Abstract

Oncolytic viruses (OVs) infect, multiply, and finally remove tumor cells selectively, causing no damage to normal cells in the process. Because of their specific features, such as, the ability to induce immunogenic cell death and to contain curative transgenes in their genomes, OVs have attracted attention as candidates to be utilized in cooperation with immunotherapies for cancer treatment. This treatment takes advantage of most tumor cells' inherent tendency to be infected by certain OVs and both innate and adaptive immune responses are elicited by OV infection and oncolysis. OVs can also modulate tumor microenvironment and boost anti-tumor immune responses. Mesenchymal stem cells (MSC) are gathering interest as promising anti-cancer treatments with the ability to address a wide range of cancers. MSCs exhibit tumor-trophic migration characteristics, allowing them to be used as delivery vehicles for successful, targeted treatment of isolated tumors and metastatic malignancies. Preclinical and clinical research were reviewed in this study to discuss using MSC-released OVs as a novel method for the treatment of cancer. Video Abstract.

Keywords: Cancer treatment; Cellular carriers; Mesenchymal stem cell; Oncolytic virotherapy; Oncolytic virus.

Fig. 1

Mesenchymal stem cell-based delivery of oncolytic virus challenges. MSCs might stimulate angiogenesis, tumor cell proliferation, and metastasis by release large numbers of cytokines and growth factors, including VEGF, FGF-2, βFGF, PDGF, IL-8, IL-6, CXCL1, CCL5, and SDF-1. MET during metastasis tighten epithelial connections and make therapy challenging. Hypoxic circumstances have been observed to decrease viral proliferation and lytic capacity. Type I IFN hinder intra-tumoral spread of the OVs, moreover, infection with double-stranded RNA leads to PKR activation in the cell. Excessive viral replication may result in premature MSC lysis and reduce the efficiency. VEGF vascular endothelial growth factor, FGF-2 fibroblast growth factor 2, PDGF platelet-derived growth factor, IL interleukin, CXCL c-x-c motif chemokine ligand 1, CCL5 c–c motif chemokine ligand, SDF-1 stromal cell-derived factor 1, MET mesenchymal-to-epithelial transitions, IFN I type I interferon, PKR RNA-dependent protein kinase, eIF2α eukaryotic initiation factor 2 α

Fig. 2

MSCs feature as OVs carriers and mechanisms of MSC-released OVs in cancer treatment. OVs are maintained by MSCs from immune system responses. MSCs migrate to the tumor site via chemotaxis. There are two major methods by which OVs destroy tumors are direct cell death and the activation of anti-tumor immunity. Tumor cells secret and release DAMPs such as HSPs, calreticulin, uric acid, and ATP and cytokines including, IFNs, TNF-α and IL-12, and PAMPs, such as nucleic acids, proteins, and viral capsid elements as a result of OVs infection and oncolysis. These compounds help counteract the immunosuppressive condition of the TME by promoting the migration and activation of MQs, NK cells, DCs, and tumor-specific cytotoxic T cells. Normal cells antiviral response also includes type I IFN which can play a significant part in anti-cancer responses by triggering immune cells inside the TME. DAMPs damage-associated molecular patterns, HSPs heat shock proteins, ATP adenosine triphosphate, IFNs interferons, TNF-α tumor necrosis factor-α, PAMPs pathogen-associated molecular patterns, MQs macrophages, NK cells natural killer cells, DCs dendritic cells, TME tumor microenvironment