Oncolytic viruses (OVs) preferentially target and kill cancer cells without affecting healthy cells through a multi-modal mechanism of action. While historically the direct killing activity of OVs was considered the primary mode of action, initiation or augmentation of a host antitumor immune response is now considered an essential aspect of oncolytic virotherapy. To improve oncolytic virotherapy, many studies focus on increasing virus replication and spread. In this article, we open for discussion the traditional dogma that correlates replication with the efficacy of OVs, pointing out several examples that oppose this principle.

Coronavirus infection in humans is usually associated to respiratory tract illnesses, ranging in severity from mild to life-threatening respiratory failure. The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses; AHR antagonists boost antiviral immunity, decrease viral titers and ameliorate Zika-induced pathology in vivo. Here we report that AHR is activated by infection with different coronaviruses, potentially impacting antiviral immunity and lung epithelial cells. Indeed, the analysis of single-cell RNA-seq from lung tissue detected increased expression of AHR and AHR transcriptional targets, suggesting AHR signaling activation in SARS-CoV-2-infected epithelial cells from COVID-19 patients. Moreover, we detected an association between AHR expression and viral load in SARS-CoV-2 infected patients. Finally, we found that the pharmacological inhibition of AHR suppressed the replication in vitro of one of the causative agents of the common cold, HCoV-229E, and the causative agent of the COVID-19 pandemic, SARS-CoV-2. Taken together, these findings suggest that AHR activation is a common strategy used by coronaviruses to evade antiviral immunity and promote viral replication, which may also contribute to lung pathology. Future studies should further evaluate the potential of AHR as a target for host-directed antiviral therapy.

Immunogenic cell death (ICD) can switch immunologically “cold” tumors “hot”, making them sensitive to immune checkpoint inhibitor (ICI) therapy. Many therapeutic platforms combine multiple modalities such as oncolytic viruses (OVs) and low-dose chemotherapy to induce ICD and improve prognostic outcomes. We previously detailed many unique properties of oncolytic bovine herpesvirus type 1 (oBHV) that suggest widespread clinical utility. Here, we show for the first time, the ability of oBHV monotherapy to induce bona fide ICD and tumor-specific activation of circulating CD8⁺ T cells in a syngeneic murine model of melanoma. The addition of low-dose mitomycin C (MMC) was necessary to fully synergize with ICI through early recruitment of CD8⁺ T cells and reduced infiltration of highly suppressive PD-1⁺ Tregs. Cytokine and gene expression analyses within treated tumors suggest that the addition of MMC to oBHV therapy shifts the immune response from predominantly anti-viral, as evidenced by a high level of interferon-stimulated genes, to one that stimulates myeloid cells, antigen presentation and adaptive processes. Collectively, these data provide mechanistic insights into how oBHV-mediated therapy modalities overcome immune suppressive tumor microenvironments to enable the efficacy of ICI therapy.

Oncolytic viruses are gaining traction as novel cancer immunotherapy tools given their ability to selectively target transformed cells. While direct tumor debulking was historically considered their primary mode of action, it is now appreciated that antitumor immunity significantly contributes to therapeutic efficacy. While T cells play a key role, less is known about humoral immunity in oncolytic virotherapy. While systemic delivery is the clinically preferred route for therapy administration, most oncolytic viruses are delivered directly to the tumor to avoid neutralization by pre-existing or therapy-induced immunity. In this review, we discuss emerging data showing the contribution of antiviral immunity to oncolytic activity along with growing evidence that questions dogma surrounding inhibitory activity of neutralizing antibodies. We further discuss how route of administration, tumor vascularization, host and cellular range, and oncolytic virus mechanism of action influence the role of the humoral immune response to therapy outcomes. We end the discussion with additional factors to consider, such as regulatory B cells, immunoglobulin isotype, Fc-mediated functions and the importance of choosing the right pre-clinical model that may contribute to overall therapy outcomes that are not routinely considered in pre-clinical and clinical studies of viral immunotherapies.