Hemagglutinating virus of Japan-envelope containing programmed cell death-ligand 1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma.

Abstract

The programmed cell death‐1/programmed cell death‐ligand 1 (PD‐1/PD‐L1) pathway is involved in preventing immune system‐mediated destruction of malignant tumors including glioblastoma. However, the therapeutic influence of PD‐1/PD‐L1 inhibition alone in glioblastoma is limited. To develop effective combination therapy involving PD‐1/PD‐L1 inhibition, we used a non‐replicating virus‐derived vector, hemagglutinating virus of Japan‐envelope (HVJ‐E), to inhibit tumor cell PD‐L1 expression by delivering siRNA targeting PD‐L1. HVJ‐E is a promising vector for efficient delivery of enclosed substances to the target cells. Moreover, HVJ‐E provokes robust antitumoral immunity by activating natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and by suppressing regulatory T lymphocytes (Treg). We hypothesized that we could efficiently deliver PD‐L1‐inhibiting siRNAs to tumor cells using HVJ‐E, and that synergistic activation of antitumoral immunity would occur due to the immunostimulating effects of HVJ‐E and PD‐1/PD‐L1 inhibition. We used artificially induced murine glioma stem‐like cells, TS, to create mouse (C57BL/6N) glioblastoma models. Intratumoral injection of HVJ‐E containing siRNA targeting PD‐L1 (siPDL1/HVJ‐E) suppressed the expression of tumor cell PD‐L1 and significantly suppressed tumor growth in subcutaneous models and prolonged overall survival in brain tumor models. Flow cytometric analyses of brain tumor models showed that the proportions of brain‐infiltrating CTL and NK cells were significantly increased after giving siPDL1/HVJ‐E; in contrast, the rate of Treg/CD4+ cells was significantly decreased in HVJ‐E‐treated tumors. CD8 depletion abrogated the therapeutic effect of siPDL1/HVJ‐E, indicating that CD8+ T lymphocytes mainly mediated this therapeutic effect. We believe that this non‐replicating immunovirotherapy may be a novel therapeutic alternative to treat patients with glioblastoma.