Oncolytic BHV-1 Is Sufficient to Induce Immunogenic Cell Death and Synergizes with Low-Dose Chemotherapy to Dampen Immunosuppressive T Regulatory Cells

Simple Summary Immunotherapy is designed to stimulate the patient's own immune system to fight their specific cancer. While immune checkpoint therapies work well for some tumors, they fail to work in tumors that are immune cold. Oncolytic viruses are viruses that preferentially target tumor cells while sparing healthy cells and can help stimulate immune responses. An oncolytic virus based on a common human herpesvirus has been granted FDA approval, and is currently being used as an intralesional cancer immunotherapy. We have previously shown that a related bovine herpesvirus has many unique properties that suggest widespread use against many types of primary and metastatic cancers. Here, we show for the first time in an immune competent mouse model that oncolytic BHV-1 can activate a type of immune response that can turn cold tumors hot. Addition of low-dose chemotherapy to oncolytic BHV-1 increases good immune responses while decreasing harmful immune responses, allowing immune checkpoint therapy to clear tumors. 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.

Automated summary

Immunotherapy stimulates the patient's immune system to fight cancer, but some tumors are immune cold and do not respond well to immune checkpoint therapies. Oncolytic viruses preferentially target tumor cells and can stimulate immune responses. An oncolytic virus based on a common human herpesvirus has been approved by the FDA and used in cancer immunotherapy. In this study, an oncolytic bovine herpesvirus is shown to activate immune responses in a mouse model, and the addition of low-dose chemotherapy enhances immune responses and enables immune checkpoint therapy to clear tumors.