Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model

Interferon gamma (IFNg) is a pleiotropic cytokine that can potentially reprogram the tumor microenvironment; however, the antitumor immunomodulatory properties of IFNg still need to be validated due to variable therapeutic outcomes in preclinical and clinical studies. We developed a replication-defi...

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Autores principales:	Olga Trofimova, Ksenija Korotkaja, Dace Skrastina, Juris Jansons, Karina Spunde, Maria Isaguliants, Anna Zajakina
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	interferon gamma cancer immunotherapy viral vectors alphavirus bone-marrow-derived macrophages spheroids Medicine R
Acceso en línea:	https://doaj.org/article/1674301669384b16bf69ae07dc1de4ce
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spelling	oai:doaj.org-article:1674301669384b16bf69ae07dc1de4ce2021-11-25T19:10:30ZAlphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model10.3390/vaccines91112472076-393Xhttps://doaj.org/article/1674301669384b16bf69ae07dc1de4ce2021-10-01T00:00:00Zhttps://www.mdpi.com/2076-393X/9/11/1247https://doaj.org/toc/2076-393XInterferon gamma (IFNg) is a pleiotropic cytokine that can potentially reprogram the tumor microenvironment; however, the antitumor immunomodulatory properties of IFNg still need to be validated due to variable therapeutic outcomes in preclinical and clinical studies. We developed a replication-deficient Semliki Forest virus vector expressing IFNg (SFV/IFNg) and evaluated its immunomodulatory antitumor potential in vitro in a model of 3D spheroids and in vivo in an immunocompetent 4T1 mouse breast cancer model. We demonstrated that SFV-derived, IFN-g-stimulated bone marrow macrophages can be used to acquire the tumoricidal M1 phenotype in 3D nonattached conditions. Coculturing SFV/IFNg-infected 4T1 spheroids with BMDMs inhibited spheroid growth. In the orthotopic 4T1 mouse model, intratumoral administration of SFV/IFNg virus particles alone or in combination with the Pam3CSK4 TLR2/1 ligand led to significant inhibition of tumor growth compared to the administration of the control SFV/Luc virus particles. Analysis of the composition of intratumoral lymphoid cells isolated from tumors after SFV/IFNg treatment revealed increased CD4<sup>+</sup> and CD8<sup>+</sup> and decreased T-reg (CD4<sup>+</sup>/CD25<sup>+</sup>/FoxP3<sup>+</sup>) cell populations. Furthermore, a significant decrease in the populations of cells bearing myeloid cell markers CD11b, CD38, and CD206 was observed. In conclusion, the SFV/IFNg vector induces a therapeutic antitumor T-cell response and inhibits myeloid cell infiltration in treated tumors.Olga TrofimovaKsenija KorotkajaDace SkrastinaJuris JansonsKarina SpundeMaria IsaguliantsAnna ZajakinaMDPI AGarticleinterferon gammacancer immunotherapyviral vectorsalphavirusbone-marrow-derived macrophagesspheroidsMedicineRENVaccines, Vol 9, Iss 1247, p 1247 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	interferon gamma cancer immunotherapy viral vectors alphavirus bone-marrow-derived macrophages spheroids Medicine R
spellingShingle	interferon gamma cancer immunotherapy viral vectors alphavirus bone-marrow-derived macrophages spheroids Medicine R Olga Trofimova Ksenija Korotkaja Dace Skrastina Juris Jansons Karina Spunde Maria Isaguliants Anna Zajakina Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model
description	Interferon gamma (IFNg) is a pleiotropic cytokine that can potentially reprogram the tumor microenvironment; however, the antitumor immunomodulatory properties of IFNg still need to be validated due to variable therapeutic outcomes in preclinical and clinical studies. We developed a replication-deficient Semliki Forest virus vector expressing IFNg (SFV/IFNg) and evaluated its immunomodulatory antitumor potential in vitro in a model of 3D spheroids and in vivo in an immunocompetent 4T1 mouse breast cancer model. We demonstrated that SFV-derived, IFN-g-stimulated bone marrow macrophages can be used to acquire the tumoricidal M1 phenotype in 3D nonattached conditions. Coculturing SFV/IFNg-infected 4T1 spheroids with BMDMs inhibited spheroid growth. In the orthotopic 4T1 mouse model, intratumoral administration of SFV/IFNg virus particles alone or in combination with the Pam3CSK4 TLR2/1 ligand led to significant inhibition of tumor growth compared to the administration of the control SFV/Luc virus particles. Analysis of the composition of intratumoral lymphoid cells isolated from tumors after SFV/IFNg treatment revealed increased CD4<sup>+</sup> and CD8<sup>+</sup> and decreased T-reg (CD4<sup>+</sup>/CD25<sup>+</sup>/FoxP3<sup>+</sup>) cell populations. Furthermore, a significant decrease in the populations of cells bearing myeloid cell markers CD11b, CD38, and CD206 was observed. In conclusion, the SFV/IFNg vector induces a therapeutic antitumor T-cell response and inhibits myeloid cell infiltration in treated tumors.
format	article
author	Olga Trofimova Ksenija Korotkaja Dace Skrastina Juris Jansons Karina Spunde Maria Isaguliants Anna Zajakina
author_facet	Olga Trofimova Ksenija Korotkaja Dace Skrastina Juris Jansons Karina Spunde Maria Isaguliants Anna Zajakina
author_sort	Olga Trofimova
title	Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model
title_short	Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model
title_full	Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model
title_fullStr	Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model
title_full_unstemmed	Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model
title_sort	alphavirus-driven interferon gamma (ifng) expression inhibits tumor growth in orthotopic 4t1 breast cancer model
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1674301669384b16bf69ae07dc1de4ce
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Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model

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