Oncolytic herpes simplex virus HF10 (canerpaturev, C-REV) promotes accumulation of CD8+ PD-1- tumor-infiltrating T cells in PD-L1- enriched tumor microenvironment.

Oncolytic viruses (OVs) remodel the tumor microenvironment by switching a 'cold' tumor into a 'hot' tumor with high CD8+ T cell infiltration. CD8+ T cell activity plays an essential role in the antitumor efficacy of OVs. However, the activity of T cells is impaired by the PD-1/PD-L1 interaction. To date, it remains unclear why OVs alone have a significant antitumor activity even when PD-L1 expression persists on tumor or immune cells. In this study, we found that C-REV treatment significantly suppressed tumor growth, even though it induced a significant increase in PD-L1 expression in tumors in vivo as well as persistence of high PD-L1 expression on antigen-presenting cells (macrophage and dendritic cells [DCs]). Surprisingly, we observed that C-REV treatment increased the abundance of activated CD8+ PD-1- tumor-infiltrating lymphocytes (TILs) in the tumor on both the injected and contralateral sides, although infiltration of CD8+ PD-1high TILs into the tumor was observed in the control group. Moreover, the difference in PD-1 expression was observed only in tumors after treatment with C-REV, whereas most CD8+ T cells in the spleen, tumor-draining lymph nodes, and blood were PD-1-negative, and this did not change after C-REV treatment. In addition, changes in expression of TIM-3 and TIGIT were not observed on CD8+ TILs after C-REV treatment. Taken together, our findings may reveal mechanisms that allow oncolytic viruses to trigger an antitumor immune response, irrespective of a PD-L1-enriched tumor microenvironment, by recruitment of CD8+ PD-1- TILs.