Remodeling the tumor microenvironment by oncolytic viruses: beyond oncolysis of tumor cells for cancer treatment

Abstract

Tumor cells manipulate the local environment in which they grow, creating a tumor microenvironment (TME) that promotes tumor survival and metastasis. The TME is an extremely complex environment rich in immunosuppressive cells and cytokines. Various methods to therapeutically target the complicated TME are emerging as a potential approach for cancer treatment. Oncolytic viruses (OVs) are one of the most promising methods for remodeling the TME into an antitumor environment and can be used alone or in combination with other immunotherapy options. OVs replicate specifically in tumor cells and can be genetically engineered to target multiple elements of the TME simultaneously, thus representing a therapeutic with the potential to modify the TME to promote activation of antitumor immune cells and overcome tumor therapeutic resistance and recurrence. In this review, we analyze the tropism of OVs towards tumor cells and explore the interaction between OVs and immune cells, tumor stroma, vasculature and the metabolic environment in detail to help understand how OVs may be one of our most promising prospects for long-term curative therapies. We also discuss some of the challenges associated with TME therapies, and future perspectives in this evolving field.

Keywords: immunotherapy; oncolytic virotherapy; oncolytic viruses; translational medical research; tumor microenvironment.

Figure 1

Actions of oncolytic viruses. Oncolytic viruses replicate selectively in tumor cells and selectivity is determined via receptor retargeting, transcriptional retargeting, abnormal antiviral signaling pathways in tumor cells, creating replication defects in healthy cells via tissue-specific miRNA expression or viral gene deletion or targeting anti-apoptotic pathways dysregulated in tumor cells. On generation of projeny virions, tumor cells are lysed and released projeny travel to infect neighboring tumor cells. Local inflammation that results from PAMP, DAMP, tumor antigen and cytokine expression consequent to OVT causes the development of a systemic antitumor immune response that can result in a long-term antitumor effect. ADCC, antibody-dependent cellular cytotoxicity; DAMP, damage associated molecular patterns; CDC, complement-dependent cytotoxicity; DC, dendritic cell; IFN, interferon; miRNA, micro RNA; NK, natural killer; PAMP, pathogen associated molecular patterns; TAA, tumor associated antigen; TSA, tumor specific antigen.

Figure 2

The tumor microenvironment prior to and in response to oncolytic virotherapy. The ‘cold’ TME is comprised of a dense stroma and immunosuppressive cells. Antitumor immune cell infiltration is rare. Treatment with OVT can cause local vascular collapse, tumor cell death and remodeling of the suppressive immune and metabolic environment to one that favors immune-mediated tumor clearance (‘hot’). CAF, cancer associated fibroblast; DC, dendritic cell; IFN, interferon; IL, interleukin; MDSC, myeloid derived suppressor cells; NK, natural killer; OV, oncolytic viruses; OVT, OV therapy; TGF, transforming growth factor;.TME, tumor microenvironment; TReg, regulatory T cell; VEGF, vascular endothelial growth factor.