Oncolytic Reovirus-Induced Prostaglandin E2 Production in Human Tumor Cells

Oncolytic viruses, which kill tumor cells by tumor cell-specific replication, elicit superior antitumor immunity by efficiently activating the innate immune system. However, innate immunity-mediated inflammation is an undesirable consequence that often induces cellular production of immunosuppressive cellular factors. Among various immunosuppressive cellular factors, much attention has recently been focused on prostaglandin E2 (PGE2). In this study, we examined PGE2 production in human tumor cells following treatment with the mammalian orthoreovirus type 3 Dearing strain (hereafter reovirus), which has been used as an oncolytic virus in preclinical and clinical studies. Reovirus significantly induced PGE2 secretion from several types of human tumor cells in a virus titer-dependent manner. A nuclear factor-kappa B (NF-κB) inhibitor, BAY11-7082, and a cyclooxygenase 2 (COX2) inhibitor, celecoxib, significantly inhibited PGE2 secretion, indicating that NF-κB and COX2 played a crucial role in reovirus-induced PGE2 production. Moreover, UV-irradiated reovirus (UV-Reo), which lost virus replication ability, did not increase PGE2 secretion. In addition, inhibitors of cathepsins B and L, cysteine lysosomal proteases crucial for reovirus replication, significantly reduced PGE2 secretion. These results indicate that reovirus replication in tumor cells is important for reovirus-induced PGE2 production. Attention should be paid to possible PGE2 production in tumors following reovirus treatment.