*5.1. Reovirus-Induced Innate Anti-Tumour Immunity*

Immune cells and infected tumour cells secrete pro-inflammatory cytokines and chemokines in response to reovirus treatment [85–88]. This occurs via engagement of pathogen-associated molecular patterns (PAMPs; e.g., viral RNA, DNA or proteins) or damage-associated molecular patterns (DAMPs; e.g., heat-shock proteins, calreticulin, uric acid and ATP released from infected cells) with pattern recognition receptors (PRRs) [89]. As with most viral infections, the secretion of type I IFN is a key

component of the innate response to reovirus [90]. Viral dsRNA in the cytoplasm of infected cells is detected by PRRs such as RIG-I, MDA5, PKR or Toll-like receptor-3 [91,92] and triggers the transcription of type I IFNs from both infected tumour cells and immune cells; dendritic cells (DCs) and monocytes are important in the detection of reovirus and secretion of IFN-α [35,85,93]. Indeed, specific roles for RIG-I and mitochondrial antiviral-signaling protein (MAVS) but not MDA5 have been reported for reovirus activation of IRF3/IRF7, whilst reovirus activation of an NF-κB was dependent on MDA5 [76]. Moreover, it has been suggested that long reovirus dsRNA gene segments activate MDA5 while short dsRNA segments activate RIG-I [76]. Importantly, a role for RIG-I signaling has also been implicated in reovirus permissiveness of *RAS*-transformed cells; the MEK/ERK pathway—downstream of RAS—blocks signaling from RIG-I and inhibits IFN production, thus enabling reovirus replication [94]. In addition, a role for TLR-3 has been described for reovirus detection within the TME. Here, reovirus inhibited the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs) in a TLR-3-dependent manner [95].

The generation of a pro-inflammatory environment reverses the immunosuppressive state of the TME, induces cytotoxic bystander cytokine killing of tumour cells, activates and recruits innate immune effector cells to kill neoplastic cells, and facilitates the generation of an adaptive anti-tumour immune response [96–99]. Reciprocal cell-to-cell interactions between DCs and natural killer (NK) cells within the TME or tumour-draining lymph nodes, can stimulate both NK cell activation and DC maturation [85,100]; NK cell anti-tumour immunity within peripheral blood mononuclear cells (PBMCs) is mediated by type I IFN secretion from monocytes [35]. In addition to the recruitment and activation of NK cells, reovirus also activates innate T cells which are capable of eliminating tumour cells via the release of cytolytic granules [85,101]; this remains a poorly understood mechanism of action.
