Sarcoma IL-12 overexpression facilitates NK cell immunomodulation

Abstract Interleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities. Lentiviral transduction eliciting IL-12-producing human sarcoma for autologous reintroduction provides localized delivery for b...

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Autores principales:	Mary Jo Rademacher, Anahi Cruz, Mary Faber, Robyn A. A. Oldham, Dandan Wang, Jeffrey A. Medin, Nathan J. Schloemer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/977b38be6fa0433cb723324e28100a65
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spelling	oai:doaj.org-article:977b38be6fa0433cb723324e28100a652021-12-02T14:30:33ZSarcoma IL-12 overexpression facilitates NK cell immunomodulation10.1038/s41598-021-87700-22045-2322https://doaj.org/article/977b38be6fa0433cb723324e28100a652021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87700-2https://doaj.org/toc/2045-2322Abstract Interleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities. Lentiviral transduction eliciting IL-12-producing human sarcoma for autologous reintroduction provides localized delivery for both innate and adaptive immune response augmentation. Sarcoma cell lines and primary human sarcoma samples were transduced with recombinant lentivirus engineering expression of human IL-12 (hu-IL-12). IL-12 expressing sarcomas were assessed in vitro and in vivo following implantation into humanized NSG and transgenic human IL-15 expressing (NSG.Tg(Hu-IL-15)) murine models. Lentiviral transduction (LV/hu-IL-12) of human osteosarcoma, Ewing sarcoma and rhabdomyosarcoma cell lines, as well as low-passage primary human sarcomas, engendered high-level expression of hu-IL-12. Hu-IL-12 demonstrated functional viability, eliciting specific NK cell-mediated interferon-γ (IFN-γ) release and cytotoxic growth restriction of spheroids in vitro. In orthotopic xenograft murine models, the LV/hu-IL-12 transduced human sarcoma produced detectable IL-12 and elicited an IFN-γ inflammatory immune response specific to mature human NK reconstitution in the NSG.Tg(Hu-IL-15) model while restricting tumor growth. We conclude that LV/hu-IL-12 transduction of sarcoma elicits a specific immune reaction and the humanized NSG.Tg(Hu-IL-15) xenograft, with mature human NK cells, can define in vivo anti-tumor effects and systemic toxicities. IL-12 immunomodulation through autologous tumor transduction and reintroduction merits exploration for sarcoma treatment.Mary Jo RademacherAnahi CruzMary FaberRobyn A. A. OldhamDandan WangJeffrey A. MedinNathan J. SchloemerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mary Jo Rademacher Anahi Cruz Mary Faber Robyn A. A. Oldham Dandan Wang Jeffrey A. Medin Nathan J. Schloemer Sarcoma IL-12 overexpression facilitates NK cell immunomodulation
description	Abstract Interleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities. Lentiviral transduction eliciting IL-12-producing human sarcoma for autologous reintroduction provides localized delivery for both innate and adaptive immune response augmentation. Sarcoma cell lines and primary human sarcoma samples were transduced with recombinant lentivirus engineering expression of human IL-12 (hu-IL-12). IL-12 expressing sarcomas were assessed in vitro and in vivo following implantation into humanized NSG and transgenic human IL-15 expressing (NSG.Tg(Hu-IL-15)) murine models. Lentiviral transduction (LV/hu-IL-12) of human osteosarcoma, Ewing sarcoma and rhabdomyosarcoma cell lines, as well as low-passage primary human sarcomas, engendered high-level expression of hu-IL-12. Hu-IL-12 demonstrated functional viability, eliciting specific NK cell-mediated interferon-γ (IFN-γ) release and cytotoxic growth restriction of spheroids in vitro. In orthotopic xenograft murine models, the LV/hu-IL-12 transduced human sarcoma produced detectable IL-12 and elicited an IFN-γ inflammatory immune response specific to mature human NK reconstitution in the NSG.Tg(Hu-IL-15) model while restricting tumor growth. We conclude that LV/hu-IL-12 transduction of sarcoma elicits a specific immune reaction and the humanized NSG.Tg(Hu-IL-15) xenograft, with mature human NK cells, can define in vivo anti-tumor effects and systemic toxicities. IL-12 immunomodulation through autologous tumor transduction and reintroduction merits exploration for sarcoma treatment.
format	article
author	Mary Jo Rademacher Anahi Cruz Mary Faber Robyn A. A. Oldham Dandan Wang Jeffrey A. Medin Nathan J. Schloemer
author_facet	Mary Jo Rademacher Anahi Cruz Mary Faber Robyn A. A. Oldham Dandan Wang Jeffrey A. Medin Nathan J. Schloemer
author_sort	Mary Jo Rademacher
title	Sarcoma IL-12 overexpression facilitates NK cell immunomodulation
title_short	Sarcoma IL-12 overexpression facilitates NK cell immunomodulation
title_full	Sarcoma IL-12 overexpression facilitates NK cell immunomodulation
title_fullStr	Sarcoma IL-12 overexpression facilitates NK cell immunomodulation
title_full_unstemmed	Sarcoma IL-12 overexpression facilitates NK cell immunomodulation
title_sort	sarcoma il-12 overexpression facilitates nk cell immunomodulation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/977b38be6fa0433cb723324e28100a65
work_keys_str_mv	AT maryjorademacher sarcomail12overexpressionfacilitatesnkcellimmunomodulation AT anahicruz sarcomail12overexpressionfacilitatesnkcellimmunomodulation AT maryfaber sarcomail12overexpressionfacilitatesnkcellimmunomodulation AT robynaaoldham sarcomail12overexpressionfacilitatesnkcellimmunomodulation AT dandanwang sarcomail12overexpressionfacilitatesnkcellimmunomodulation AT jeffreyamedin sarcomail12overexpressionfacilitatesnkcellimmunomodulation AT nathanjschloemer sarcomail12overexpressionfacilitatesnkcellimmunomodulation
_version_	1718391207658258432

Sarcoma IL-12 overexpression facilitates NK cell immunomodulation

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