Oncolytic Reovirus Inhibits Immunosuppressive Activity of Myeloid-Derived Suppressor Cells in a TLR3-Dependent Manner.

Oncolytic reovirus, which possesses 10 segments of dsRNA genome, mediates antitumor effects via not only virus replication in a tumor cell-specific manner, but also activation of antitumor immunity; however, the mechanism(s) of reovirus-induced activation of antitumor immunity have not been fully elucidated. Recent studies have demonstrated that overcoming an immunosuppressive environment in tumor-bearing hosts is important to achieve efficient activation of antitumor immunity. Among the various types of cells involved in immunosuppression, it has been revealed that myeloid-derived suppressor cells (MDSCs) are significantly increased in tumor-bearing hosts and play crucial roles in the immunosuppression in tumor-bearing hosts.

Cationic liposome-mediated delivery of reovirus enhances the tumor cell-killing efficiencies of reovirus in reovirus-resistant tumor cells.

Reovirus induces tumor cell death efficiently and specifically, and thus is currently undergoing clinical testing as an anticancer agent. In the intracellular trafficking of reovirus, proteolytic disassembly of reovirus capsid-proteins and subsequent penetration of viral particles into the cytosol are crucial steps. Cathepsins B and L are largely responsible for the proteolytic disassembly of reovirus.

Proteolytic disassembly of viral outer capsid proteins is crucial for reovirus-mediated type-I interferon induction in both reovirus-susceptible and reovirus-refractory tumor cells.

Oncolytic reovirus induces innate immune responses, which contribute to the antitumor activity of reovirus, following in vivo application. Reovirus-induced innate immune responses have been relatively well characterized in immune cells and mouse embryonic fibroblasts cells; however, the mechanisms and profiles of reovirus-induced innate immune responses in human tumor cells have not been well understood. In particular, differences in reovirus-induced innate immune responses between reovirus-susceptible and reovirus-refractory tumor cells remain unknown, although the intracellular trafficking of reovirus differs between these tumor cells.