**5. TME Make over by Oncolytic Viruses**

OV infection leads to a cascade of inflammatory events, stimulating innate and adaptive immune responses, and thus changing the cytokine, chemokine and cellular composition of tumours. Viral nucleic acids serve as pathogen-associated molecular patterns (PAMPs) to activate cytoplasmic RNA and DNA sensors and Toll-like receptors (TLRs), converging on TRIF and MyD88 to activate type I IFN signaling [62,63]. OV infection upregulates calreticulin (CRT) on the cell surface, and oncolysis releases adenosine triphosphate (ATP) and high-mobility group box 1 (HMGB1) into the extracellular environment, all members of the danger-associated molecular pattern (DAMP) family [64,65]. Together, in concert with type I IFN, these signals promote the recruitment and maturation of DCs which take up virus and tumour debris, traffic antigen back to lymph nodes, and prime naïve T cells. Although all CXCR3 ligands are induced by IFNγ, CXCL10 and 11 are directly agonized by type I IFN [66].

Thus, infection leads to a global change in the cellular composition of the tumour and the corresponding derived soluble mediators. Mouse models have demonstrated that OVs promote the infiltration and activation of CD8 T cells, CD11c+ DC, NK cells, M1 like macrophages, and concomitantly reduce the proportion of Tregs and MDSCs [67–74]. Although a large fraction of infiltrating T cells is likely to be specific to viral antigens, oncolysis can act as a tumour antigen agnostic vaccine, priming T cells against public and private neoantigens [73,75]. Oncolytic infection and type I IFN concomitantly induce the upregulation of checkpoint receptor ligands such as PDL1, and thus combination therapy with pharmacologic or viral expression of checkpoint blocking antibodies with vaccinia [67], VSV [68,76], reovirus [77], measles [70,78], HSV [72] and NDV [71] have provided superior tumour outcomes. Immune correlative studies in the clinical setting have corroborated preclinical findings, showing that talimogene laherparepvec (HSV) and reovirus treatment promotes an increase in CD8 T cell density in post treatment biopsies [79,80], and measles treatment facilitates T cell priming against tumour antigens [81]. The representation of virus specific or tumour antigen specific T cells which infiltrate into a tumour is not well characterized, however is likely to be skewed toward viral specificities due to high level expression of viral epitopes which are not subject to tolerance mechanisms.
