Abstract
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.
Highlights
The tumor microenvironment (TME) and immune cell composition play essential roles in tumor development
The 4T1/eGFP spheroids were infected with Semliki Forest virus (SFV)/DS-Red virus (1 × 105 i.u. per well) and DS-Red gene expression was analyzed by live fluorescence confocal microscopy at 48 h post-infection (Figure 1a, maximum intensity projection images)
We concluded that the SFV vector infects the 4T1 spheroids in 3D conditions; virus spread within the spheroid was limited
Summary
The tumor microenvironment (TME) and immune cell composition play essential roles in tumor development. Immunotherapy is a novel strategy for cancer treatment aimed at modifying the TME and (re)programming immune cells. Pleotropic cytokines represent key instruments of immunotherapy because they allow the programming of the TME for cancer treatment due to their ability to mediate communication between cells and modify their functions [1,2]. During the last 20 years, preclinical and clinical studies have examined the therapeutic impacts of IFNg alone or in combination with chemotherapy and immunotherapy. Despite these efforts, there is still no definite conclusion on the efficacy of IFNg in cancer therapy [5,6,7]. The IFNg-related induction of proinflammatory responses was shown to lead to antitumor and protumor effects [8]
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