The antiviral immune forces awaken in the cancer wars

Pyeon, Dohun; Vu, Lexi; Giacobbi, Nicholas S.; Westrich, Joseph A.

doi:10.1371/journal.ppat.1008814

Cited by 9 publications

(6 citation statements)

References 38 publications

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“…IRF7 translocated to the nucleus and up-regulated interferons (IFN) and interferon-stimulated genes (ISG) which include dsRNA sensors and other upstream components in a feedback loop, triggering an innate immune response including presentation of peptides produced from the cancer/testis antigen (CTA) genes at the surface and cell-cell signalling [ 11 , 12 ]. Association of the CTAs with immune response to viral infection has also been reported [ 13 , 14 ]. The extent to which these effects are due to loss of DNA methylation only, or to secondary effects of the inhibitors is currently unclear though, since the effects have not been fully characterized in cells carrying DNMT1 mutations [ 11 , 15 ] and 5-AZA-CdR is known to affect levels of the histone methyltransferase G9a [ 16 ].…”

Section: Introductionmentioning

confidence: 95%

The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells

et al. 2023

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While epigenetic mechanisms such as DNA methylation and histone modification are known to be important for gene suppression, relatively little is still understood about the interplay between these systems. The UHRF1 protein can interact with both DNA methylation and repressive chromatin marks, but its primary function in humans has been unclear. To determine what that was, we first established stable UHRF1 knockdowns (KD) in normal, immortalized human fibroblasts using targeting shRNA, since CRISPR knockouts (KO) were lethal. Although these showed a loss of DNA methylation across the whole genome, transcriptional changes were dominated by the activation of genes involved in innate immune signalling, consistent with the presence of viral RNA from retrotransposable elements (REs). We confirmed using mechanistic approaches that 1) REs were demethylated and transcriptionally activated; 2) this was accompanied by activation of interferons and interferon-stimulated genes and 3) the pathway was conserved across other adult cell types. Restoring UHRF1 in either transient or stable KD systems could abrogate RE reactivation and the interferon response. Notably, UHRF1 itself could also re-impose RE suppression independent of DNA methylation, but not if the protein contained point mutations affecting histone 3 with trimethylated lysine 9 (H3K9me3) binding. Our results therefore show for the first time that UHRF1 can act as a key regulator of retrotransposon silencing independent of DNA methylation.

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Section: Introductionmentioning

confidence: 95%

The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells

et al. 2023

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“…), which correlated with clinical observations [22]. A promising way to enhance the antitumour effects of IFNg along with the inhibition of its potential protumour effects is shown to be a complex treatment with immune checkpoint inhibitors [23][24][25], chemoimmunotherapy [26,27] alone or in combination with oncolytic viral vectors additionally inducing the innate immunity in tumours [28,29].…”

Section: Introductionmentioning

confidence: 61%

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

Trofimova¹,

Korotkaja²,

Skrastiņa³

et al. 2021

Preprint

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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.

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“…), which correlated with clinical observations [22]. A promising way to enhance the antitumor effects of IFNg along with the inhibition of its potential protumor effects has been shown to be a complex treatment with immune checkpoint inhibitors [23][24][25] and chemoimmunotherapy [26,27] alone or in combination with oncolytic viral vectors, additionally inducing the innate immunity in tumors [28,29].…”

Section: Introductionmentioning

confidence: 63%

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

et al. 2021

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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.

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The antiviral immune forces awaken in the cancer wars

Cited by 9 publications

References 38 publications

The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells

The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells

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

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

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