Dengue virus induces human immune cells to secrete factors capable of tumor cell killing and activation of effector cells against treatment-resistant tumors

Abstract

Abstract The use of oncolytic viruses (OVs) as immunotherapies has reinvigorated interest in microbial-based cancer therapies (MBCTs). However, thus far only one OV is FDA-approved and improvement in overall survival is experienced by a small proportion of treated patients. Seeking to take a bold approach, we pursued using Dengue virus (DV) as a novel cancer virotherapy. Thus far, DV has had little to no exploration in cancer, despite being well-studied in the vaccine context, where it demonstrates an outstanding safety profile. In our studies, we identified DV as having the ability to cause tumor cell death. Importantly, co-culture of human peripheral blood mononuclear cells (PBMCs) with DV resulted in cytokine production (including IL-2, IL-6, IL-7, IL-12, TNFα, and IFNγ) rather than cell death. We observed that supernatants from such co-cultures at 72 hours (m.o.i. of 2.0) were able to stimulate T cell- and NK cell-mediated killing of 624.28 melanoma cells, which are resistant to killing due to deletion of the HLA A2.1 gene. Surprisingly, these supernatants alone were also able to cause 624.28 cell death without effector cells or DV present. To determine whether DV could likewise reduce in vivo tumor growth, we utilized our DV plus dendritic cell (DC) platform, in which bone marrow-derived DCs deliver a relevant tumor antigen. C57BL/6 (B6) mice were challenged with B16 cells (5×104) via tail vein injection, resulting in lung melanoma foci. DV treatment (106 pfu, subcutaneous) with gp100-loaded DCs (6×106 via infusion) reduced melanoma foci in the lung by 51% (p<0.05). Future research will focus on mechanisms underlying DV-driven anti-tumor immune responses and tumor cell killing, with the intent of translating these findings to the clinic.