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Article

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

1
Latvian Biomedical Research and Study Centre, Ratsupites Str.1. k.1., LV-1067 Riga, Latvia
2
Institute of Microbiology and Virology, Riga Stradins University, LV-1007 Riga, Latvia
3
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
4
N.F. Gamaleya National Research Center for Epidemiology and Microbiology, 123 098 Moscow, Russia
*
Author to whom correspondence should be addressed.
Academic Editors: Kyong-Hwa Park and Ralph A. Tripp
Vaccines 2021, 9(11), 1247; https://doi.org/10.3390/vaccines9111247
Received: 25 July 2021 / Revised: 10 September 2021 / Accepted: 18 October 2021 / Published: 27 October 2021
(This article belongs to the Special Issue Perspective Technologies of Vaccination and Immunotherapy)
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+ and CD8+ and decreased T-reg (CD4+/CD25+/FoxP3+) 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. View Full-Text
Keywords: interferon gamma; cancer immunotherapy; viral vectors; alphavirus; bone-marrow-derived macrophages; spheroids; CD38; Pam3CSK4 interferon gamma; cancer immunotherapy; viral vectors; alphavirus; bone-marrow-derived macrophages; spheroids; CD38; Pam3CSK4
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MDPI and ACS Style

Trofimova, O.; Korotkaja, K.; Skrastina, D.; Jansons, J.; Spunde, K.; Isaguliants, M.; Zajakina, A. Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model. Vaccines 2021, 9, 1247. https://doi.org/10.3390/vaccines9111247

AMA Style

Trofimova O, Korotkaja K, Skrastina D, Jansons J, Spunde K, Isaguliants M, Zajakina A. Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model. Vaccines. 2021; 9(11):1247. https://doi.org/10.3390/vaccines9111247

Chicago/Turabian Style

Trofimova, Olga, Ksenija Korotkaja, Dace Skrastina, Juris Jansons, Karina Spunde, Maria Isaguliants, and Anna Zajakina. 2021. "Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model" Vaccines 9, no. 11: 1247. https://doi.org/10.3390/vaccines9111247

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