While precisely how TAP inhibitors like UL

While precisely how TAP inhibitors like UL49.5 augment OV therapy and promote CD8+-dependent anti-tumor immune responses are unknown, evading CTLs is likely important. By shielding infected cells from elimination, TAP inhibitor armed OVs persist longer (Fig. 2c). Importantly, BV49.5 was not detectably more pathogenic than BV49.5 and never spread to contralateral, untreated tumors despite replicating to greater levels in directly-injected, treated tumors. Furthermore, no adverse effects associated with HSV-1 pathogenesis and virulence were observed throughout this study in any of the treated mice, even after multiple injections and upon CD8+ T cell depletion. This is consistent with OV replication being limited to the treated tumor and restricted OV growth and spread in normal tissue as has been reported for numerous HSV-1 Δ34.5 OVs (Rampling et al., 2000; Markert et al., 2000; Taneja et al., 2001; Todo et al., 2001; Hu et al., 2006; Senzer et al., 2009; Harrington et al., 2010; Andtbacka et al., 2015). Longer OV persistence within tumors could cause greater oncolysis in the primary tumor despite preexisting antiviral immunity. This likely generates more tumor associated purchase Calcitriol (TAA) available for cross-presentation by dendritic cells (DCs) to anti-tumor CD8+ CTL. Significantly, downregulating antigen presentation and evading anti-viral CD8+ CTLs by a TAP inhibitor-armed OV resembles a mechanism used by some advanced tumors to evade elimination by anti-tumor CTL (Leone et al., 2013). Although TAA display is reduced in tumors with antigen presentation defects, antigen presentation is not eliminated so long as peptides are processed and access MHC class I via a TAP-independent manner. Indeed, TAP-deficient tumors instead display an MHC class I - peptide antigen repertoire derived from alternative sources, including signal peptides generated by co-translational cleavage in the ER lumen or peptides generated in other compartments (trans Golgi, endosomal) that subsequently enter the ER (reviewed inOliveira and van Hall, 2013). Display of an alternate peptide repertoire in TAP-inhibited cells, including those ectopically expressing BHV-1 UL49.5, reportedly contributes to immune recognition of TAP-inhibited cells by CD8+ T-cells (Lampen et al., 2010). Perhaps remodeling MHC class I — peptide antigen repertoires following TAP-inhibitor armed OV treatment might in part influence immunotherapeutic, anti-tumor responses (van Hall et al., 2006). Our findings are also consistent with results showing that evading T-cell responses is critical for superinfecting monkeys previously colonized by the related herpesvirus cytomegalovirus (Hansen et al., 2010), as HSV-1 OV treatment of HSV-1 positive subjects and initially HSV-1 negative patients that seroconvert after the first dose can be considered a form of superinfection. Furthermore, they support a model where an OV expressing the UL49.5 TAP inhibitor to evade CD8+ CTLs exerts both local and global effects, facilitating viral replication and direct oncolysis within a tumor thus stimulating a global anti-tumor immune response. Finally, they establish that the systemically-acting, immunotherapeutic power of local OV administration is effectively enabled by harnessing the natural ability of HSV to persist in the face of CD8+ T-cell responses. TAP-inhibitor armed OVs might better synergize with immune checkpoint inhibitors (Zamarin et al., 2014), or possibly be sufficiently potent as single agents compared to OVs unable to inhibit TAP.
Conclusions Oncolytic viruses (OVs) offer advantages over traditional cancer therapies by selectively killing tumor cells and stimulating anti-tumor immune responses. However, vulnerability to CD8+ T-cell clearance limits therapeutic responses to OVs. Using a herpes simplex virus-1 OV model, we engineer an OV that evades CD8+ T-cells by expressing a herpesvirus-encoded inhibitor of TAP (transporter associated with antigen processing). Our results show OVs that inhibit TAP demonstrate greater efficacy treating bladder and breast cancer in a manner dependent upon CD8+ T-cell immune responses in pre-clinical mouse models. Moreover, they were better able to stimulate systemic anti-tumor responses that reduced distant, untreated tumors and natural metastases. This establishes that arming OVs to evade CD8+ T cells as an effective OV immunotherapy strategy.