Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 27 August 2021 / Approved: 30 August 2021 / Online: 30 August 2021 (10:18:08 CEST)

How to cite: Trofimova, O.; Korotkaja, K.; Skrastina, D.; Jansons, J.; Spunde, K.; Isaguliants, M.; Zajakina, A. Alphavirus-driven Interferon Gamma (IFNg) Expression Inhibits Tumour Growth in Orthotopic 4T1 Breast Cancer Model. Preprints 2021, 2021080536 (doi: 10.20944/preprints202108.0536.v1). Trofimova, O.; Korotkaja, K.; Skrastina, D.; Jansons, J.; Spunde, K.; Isaguliants, M.; Zajakina, A. Alphavirus-driven Interferon Gamma (IFNg) Expression Inhibits Tumour Growth in Orthotopic 4T1 Breast Cancer Model. Preprints 2021, 2021080536 (doi: 10.20944/preprints202108.0536.v1).

Abstract

Interferon gamma (IFNg) is a pleiotropic cytokine that can potentially reprogramme the tumour microenvironment. However, the antitumour 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 antitumour potential in vitro in a model of 3D spheroids and in vivo in immunocompetent 4T1 mouse breast cancer model. We demonstrated that SFV-derived IFN-g stimulated bone marrow macrophages 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, intratumoural administration of SFV/IFNg virus particles alone or in combination with the Pam3CSK4 TLR2/1 ligand led to significant inhibition of tumour growth compared to the administration of the control SFV/Luc virus particles. Analysis of the composition of intra-tumoural lymphoid cells isolated from tumours after SFV/IFNg treatment revealed an increase in CD4+ and CD8+ and a decrease in 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 antitumour T-cell response and inhibits myeloid cell infiltration in treated tumours.

Keywords

interferon gamma; cancer immunotherapy; viral vectors; alphavirus; bone marrow-derived macrophages; spheroids; CD38; Pam3CSK4

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