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.

• Authors: Narushi Sugii, Masahide Matsuda, Genki Okumura, Akira Shibuya, Eiichi Ishikawa, Yasufumi Kaneda, Akira Matsumura
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 1 Pg. 81-90 (Jan 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 33155337 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• Programmed Cell Death 1 Receptor
• RNA, Small Interfering
• Viral Envelope Proteins

Topics

• Animals
• B7-H1 Antigen (immunology)
• Brain Neoplasms (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Female
• Genetic Vectors (immunology)
• Glioblastoma (immunology)
• Glioma (immunology)
• Immune Tolerance (immunology)
• Japan
• Killer Cells, Natural (immunology)
• Lymphocyte Activation (immunology)
• Mice
• Mice, Inbred C57BL
• Oncolytic Virotherapy (methods)
• Programmed Cell Death 1 Receptor (immunology)
• RNA, Small Interfering (immunology)
• Sendai virus (immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Viral Envelope Proteins (immunology)