Supplementary MaterialsSupplemental Material koni-08-07-1591875-s001. in C57/BL6J mice (Suppl Physique 1). Once tumors were palpable, mice were mock-treated, treated with T-VEC or treated with murine PD-1 antibody as explained in Methods. STINGlo D4M3A melanoma tumors did not respond to PD-1 blockade as no significant differences were observed between mock treated mice (Suppl Physique 3A) and mice treated with PD-1 blockade (Suppl Physique 3B). This was consistent with previous reports showing D4M3A cell collection does not respond to PD-1 blockade.30 We did, however, observe significant tumor growth reduction in T-VEC treated mice (Suppl Determine 2C). T-VEC treatment significantly reduced tumor growth and completely eliminated tumors in 1/5 treated mice, while treatment with PD-1 antibody experienced no significant effect on tumor growth. To determine if T-VEC treatment was associated with systemic anti-tumor activity, we implanted D4M3A tumors in both the right and left flanks of C57/BL6J mice. T-VEC was injected into the right flank palpable tumors according to the study schema shown in Physique 6A. T-VEC treatment significantly reduced tumor volume in both injected and un-injected contralateral tumors compared to mock treated mice (Physique 6BCC). T-VEC was associated with total regression in 3/9 injected tumors and 1/9 un-injected tumors. T-VEC treatment also significantly enhanced survival of mice compared to mock treatment (Physique 6C). These data show that T-VEC induced anti-tumor activity in STINGlo melanoma tumors that are resistant to PD-1 blockade. Open in a separate window Physique 6. T-VEC has therapeutic activity in STING^lo melanoma treatment with T-VEC, highlighting the natural counter-regulatory mechanism wherein viral-induced type 1 interferons inhibit T cells through engagement of Calcrl the PD-1/PD-L1 pathway. While BI207127 (Deleobuvir) this may limit the therapeutic activity of oncolytic viruses, it also provides strong biologic rational for combining T-VEC with PD-1/PD-L1 blockade. While these data are important for understanding how T-VEC contributes to the anti-tumor response, other oncolytic viruses may mediate host anti-tumor immunity through other mechanisms. For example, in a recent report of an oncolytic Newcastle disease computer virus (NDV) in lung malignancy cell lines, NDV induced DAMP release as seen with T-VEC but autophagy also played an important role in mediating cell death.33 As the field develops, it will be critical to confirm how tumor cells die with each oncolytic computer virus to better identify relevant clinical indications and optimize combination approaches. The initial response to HSV-1 contamination occurs when viral DNA is usually sensed by elements of BI207127 (Deleobuvir) the anti-viral machinery.34 Indeed, one of the reasons for selective tumor cell replication for many DNA-based oncolytic viruses is due to deficiencies in anti-viral machinery elements.35,36 Using a panel of human melanoma cell lines with variable sensitivity to T-VEC infection, we observed an inverse correlation between STING expression and T-VEC permissiveness. We did not find any impact of PKR or cGAS on T-VEC-mediated killing suggesting that STING may be particularly important. BI207127 (Deleobuvir) Recent studies have also recognized STING expression as an integral intracellular factor in promoting lymphocyte recruitment to tumors and supporting sensitivity to immunotherapy.10 In tumor cells, STING may be triggered by aberrant tumor cell DNA, which then activates cytokines that coordinate BI207127 (Deleobuvir) with extrinsic STING to induce antigen presentation and trigger host anti-tumor immunity. This pathway.