Cargando…

IM-6 HVJ-E containing PD-L1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma

Inactivated Sendai virus particle, hemagglutinating virus of Japan-envelope (HVJ-E), is a non-replicating virus-derived vector, in which the genomic RNA of Sendai virus (HVJ) has been destroyed. HVJ-E is a promising vector that enables the highly efficient and safe introduction of enclosed molecules...

Descripción completa

Detalles Bibliográficos
Autores principales: Sugii, Narushi, Matsuda, Masahide, Okumura, Genki, Shibuya, Akira, Ishikawa, Eiichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8648244/
http://dx.doi.org/10.1093/noajnl/vdab159.028
_version_ 1784610765866532864
author Sugii, Narushi
Matsuda, Masahide
Okumura, Genki
Shibuya, Akira
Ishikawa, Eiichi
author_facet Sugii, Narushi
Matsuda, Masahide
Okumura, Genki
Shibuya, Akira
Ishikawa, Eiichi
author_sort Sugii, Narushi
collection PubMed
description Inactivated Sendai virus particle, hemagglutinating virus of Japan-envelope (HVJ-E), is a non-replicating virus-derived vector, in which the genomic RNA of Sendai virus (HVJ) has been destroyed. HVJ-E is a promising vector that enables the highly efficient and safe introduction of enclosed molecules such as RNA into target cells. Moreover, HVJ-E provokes robust antitumoral immunity by activating natural killer (NK) cells and CD8+ T lymphocytes and their induction into the tumor periphery, and by suppressing regulatory T lymphocytes (Treg) locally in the tumor. In the present study, we investigated a novel combination of antitumor immunotherapy by the antitumor immune-activating effect of HVJ-E itself with the inhibition of tumor PD-L1 molecule expression. We confirmed that intratumoral injection of HVJ-E containing siRNA targeting PD-L1 (siPDL1/HVJ-E) inhibited tumor PD-L1 protein expression in a mouse subcutaneous tumor model using TS, a mouse glioma stem-like cell. We conducted treatment experiments in the mouse brain tumor model in three groups: control group (PBS), siNC/HVJ-E group (negative control siRNA + HVJ-E), and siPDL1/HVJ-E group. We obtained a significant prolongation of overall survival in the siPDL1/HVJ-E group. Flow cytometric analyses of brain tumor models showed that the proportions of brain-infiltrating CD8+ T lymphocytes and NK cells were significantly increased after giving siPDL1/HVJ-E; in contrast, the rate of Treg/CD4+ lymphocytes was significantly decreased in HVJ-E-treated tumors (siNC/HVJ-E and siPDL1/HVJ-E). No difference was observed in the proportions of macrophages or M2 macrophages. 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. The full article has been published (Cancer Science. 2021 Jan;112(1):81–90).
format Online
Article
Text
id pubmed-8648244
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-86482442021-12-07 IM-6 HVJ-E containing PD-L1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma Sugii, Narushi Matsuda, Masahide Okumura, Genki Shibuya, Akira Ishikawa, Eiichi Neurooncol Adv Supplement Abstracts Inactivated Sendai virus particle, hemagglutinating virus of Japan-envelope (HVJ-E), is a non-replicating virus-derived vector, in which the genomic RNA of Sendai virus (HVJ) has been destroyed. HVJ-E is a promising vector that enables the highly efficient and safe introduction of enclosed molecules such as RNA into target cells. Moreover, HVJ-E provokes robust antitumoral immunity by activating natural killer (NK) cells and CD8+ T lymphocytes and their induction into the tumor periphery, and by suppressing regulatory T lymphocytes (Treg) locally in the tumor. In the present study, we investigated a novel combination of antitumor immunotherapy by the antitumor immune-activating effect of HVJ-E itself with the inhibition of tumor PD-L1 molecule expression. We confirmed that intratumoral injection of HVJ-E containing siRNA targeting PD-L1 (siPDL1/HVJ-E) inhibited tumor PD-L1 protein expression in a mouse subcutaneous tumor model using TS, a mouse glioma stem-like cell. We conducted treatment experiments in the mouse brain tumor model in three groups: control group (PBS), siNC/HVJ-E group (negative control siRNA + HVJ-E), and siPDL1/HVJ-E group. We obtained a significant prolongation of overall survival in the siPDL1/HVJ-E group. Flow cytometric analyses of brain tumor models showed that the proportions of brain-infiltrating CD8+ T lymphocytes and NK cells were significantly increased after giving siPDL1/HVJ-E; in contrast, the rate of Treg/CD4+ lymphocytes was significantly decreased in HVJ-E-treated tumors (siNC/HVJ-E and siPDL1/HVJ-E). No difference was observed in the proportions of macrophages or M2 macrophages. 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. The full article has been published (Cancer Science. 2021 Jan;112(1):81–90). Oxford University Press 2021-12-06 /pmc/articles/PMC8648244/ http://dx.doi.org/10.1093/noajnl/vdab159.028 Text en © The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Supplement Abstracts
Sugii, Narushi
Matsuda, Masahide
Okumura, Genki
Shibuya, Akira
Ishikawa, Eiichi
IM-6 HVJ-E containing PD-L1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma
title IM-6 HVJ-E containing PD-L1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma
title_full IM-6 HVJ-E containing PD-L1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma
title_fullStr IM-6 HVJ-E containing PD-L1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma
title_full_unstemmed IM-6 HVJ-E containing PD-L1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma
title_short IM-6 HVJ-E containing PD-L1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma
title_sort im-6 hvj-e containing pd-l1 sirna inhibits immunosuppressive activities and elicits antitumor immune responses in glioma
topic Supplement Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8648244/
http://dx.doi.org/10.1093/noajnl/vdab159.028
work_keys_str_mv AT sugiinarushi im6hvjecontainingpdl1sirnainhibitsimmunosuppressiveactivitiesandelicitsantitumorimmuneresponsesinglioma
AT matsudamasahide im6hvjecontainingpdl1sirnainhibitsimmunosuppressiveactivitiesandelicitsantitumorimmuneresponsesinglioma
AT okumuragenki im6hvjecontainingpdl1sirnainhibitsimmunosuppressiveactivitiesandelicitsantitumorimmuneresponsesinglioma
AT shibuyaakira im6hvjecontainingpdl1sirnainhibitsimmunosuppressiveactivitiesandelicitsantitumorimmuneresponsesinglioma
AT ishikawaeiichi im6hvjecontainingpdl1sirnainhibitsimmunosuppressiveactivitiesandelicitsantitumorimmuneresponsesinglioma