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

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

Cancer science (2020-11-07)
Narushi Sugii, Masahide Matsuda, Genki Okumura, Akira Shibuya, Eiichi Ishikawa, Yasufumi Kaneda, Akira Matsumura
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.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
Penicillin-Streptomycin, with 10,000 units penicillin and 10 mg streptomycin per mL in 0.9% NaCl, 0.1 μm filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
Dulbecco′s Modified Eagle′s Medium/Nutrient Mixture F-12 Ham, With L-glutamine, 15 mM HEPES, and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture