A structural “star” in interferon gamma signaling

Hertzog, Paul J.; Weerd, Nicole A. de

doi:10.1111/imcb.12255

Cited by 4 publications

(4 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IFN-γ activates interferon-gamma receptors in various immune cells, including T lymphocytes, cytotoxic T lymphocytes (CTLs), natural killer cells (NK), natural killer Tcells (NKT), dendritic cells (DCs), B-cells, and myeloid cells [36,55]. IFN-γ binds to the IFNGR1/IFNGR2 heterodimer receptor to activate Janus kinases JAK1 and JAK2 and the signal transducer and activator of transcription STAT1 and STAT3 pathways (Figure 8) [35,56]. We examined whether high levels of TGFB2 and low levels of either JAK1 or STAT1 also relate to worse survival outcomes and, hence, suggest that the IFNGR2/TGFB2 interaction has functional significance.…”

Section: Discussionmentioning

confidence: 99%

“…Opposite effects of increasing TGFB2 and IFNGR2/JAK1/STAT1 mRNA levels on OS outcomes in pbDMG patients. The schematic displays simplified models for the activation of the interferon-gamma receptor [56] and transforming growth factor beta receptor [64] on the plasma membrane by their respective ligands, IFN-γ (IFNG) and TGFB2, leading to a more favorable OS for IFNGR2/JAK1/STAT1 and a worse OS for TGFB2. The red boxes depict significant prognostic indicators.…”

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Transforming Growth Factor Beta 2 (TGFB2) and Interferon Gamma Receptor 2 (IFNGR2) mRNA Levels in the Brainstem Tumor Microenvironment (TME) Significantly Impact Overall Survival in Pediatric DMG Patients

Qazi,

Talebi,

Trieu

2024

Biomedicines

View full text Add to dashboard Cite

This hypothesis-generating study characterized the mRNA expression profiles and prognostic impacts of antigen-presenting cell (APC) markers (CD14, CD163, CD86, and ITGAX/CD11c) in pediatric brainstem diffuse midline glioma (pbDMG) tumors. We also assessed the mRNA levels of two therapeutic targets, transforming growth factor beta 2 (TGFB2) and interferon gamma receptor 2 (IFNGR2), for their biomarker potentials in these highly aggressive pbDMG tumors. The expressions of CD14, CD163, and ITGAX/CD11c mRNAs exhibited significant decreases of 1.64-fold (p = 0.037), 1.75-fold (p = 0.019), and 3.33-fold (p < 0.0001), respectively, in pbDMG tumors relative to those in normal brainstem/pons samples. The pbDMG samples with high levels of TGFB2 in combination with low levels of APC markers, reflecting the cold immune state of pbDMG tumors, exhibited significantly worse overall survival outcomes at low expression levels of CD14, CD163, and CD86. The expression levels of IFNGR2 and TGFB2 (1.51-fold increase (p = 0.002) and 1.58-fold increase (p = 5.5 × 10−4), respectively) were significantly upregulated in pbDMG tumors compared with normal brainstem/pons samples. We performed multivariate Cox proportional hazards modelling that showed TGFB2 was a prognostic indicator (HR for patients in the TGFB2high group of pbDMG patients = 2.88 (1.12–7.39); p = 0.028) for poor overall survival (OS) and was independent of IFNGR2 levels, the age of the patient, and the significant interaction effect observed between IFNGR2 and TGFB2 (p = 0.015). Worse survival outcomes in pbDMG patients when comparing high versus low TGFB2 levels in the context of low IFNGR2 levels suggest that the abrogation of the TGFB2 mRNA expression in the immunologically cold tumor microenvironment can be used to treat pbDMG patients. Furthermore, pbDMG patients with low levels of JAK1 or STAT1 mRNA expression in combination with high levels of TGFB2 also exhibited poor OS outcomes, suggesting that the inclusion of (interferon-gamma) IFN-γ to stimulate and activate JAK1 and STAT1 in anti-tumor APC cells present the brainstem TME can enhance the effect of the TGFB2 blockade.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Transforming Growth Factor Beta 2 (TGFB2) and Interferon Gamma Receptor 2 (IFNGR2) mRNA Levels in the Brainstem Tumor Microenvironment (TME) Significantly Impact Overall Survival in Pediatric DMG Patients

Qazi,

Talebi,

Trieu

2024

Biomedicines

View full text Add to dashboard Cite

show abstract

“… TGFB2 and IFNGR2/STAT1/IRF1/IRF5 mRNA levels prognostically impact OS outcomes in LGG patients. The schematic displays simplified models for the activation of the interferon-gamma receptor [ 56 ] and transforming growth factor beta receptor [ 57 ] on the plasma membrane by their respective ligands, IFN-γ (IFNG) and TGFB2, leading to worse OS at increased mRNA levels of IFNGR2/STAT1/IRF1/IRF5 and TGFB2 (indicated by red boxes). IFN-γ dimer signals bind to the extracellular domains of a cell surface receptor composed of an IFNGR1 and IFNGR2 tetrameric structure (blue structure).…”

Section: Figurementioning

confidence: 99%

Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas

Trieu,

Maida,

Qazi

2024

Cancers

View full text Add to dashboard Cite

LGG tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. We conducted a study analyzing mRNA expression datasets from the UCSC Xena web platform. To screen for upregulated genes, we sought to compare normal brain tissue with LGG tumor samples. We also used cBioportal to determine the relationship between mRNA expression levels of 513 LGG patients and their overall survival (OS) outcomes. Three tumor-associated macrophage (TAM) markers, MSR1/CD204, CD86, and CD68, exhibited a 6-fold (p < 0.0001), 8.9-fold (p < 0.0001), and 15.6-fold increase in mRNA expression levels, respectively, in LGG tumors. In addition, both TGFB1 (4.1-fold increase, p < 0.0001) and TGFB2 (2.2-fold increase, p < 0.0001) ligands were also upregulated in these tumors compared to normal brain tissue, suggesting that TGFB ligands are pivotal in establishing an immunosuppressive, angiogenic, and pro-tumorigenic TME in gliomas mediated through TAMs. In addition, mRNA upregulation of interferon-gamma receptors, IFNGR1 and IFNGR2, and the downstream signaling molecules STAT1, IRF1, and IRF5, pointed to an essential role for IFN-γ mediated remodeling of the TME. Interestingly, the mRNA expression of a tumor-associated antigen, CD276/B7-H3, showed a significant (p < 0.0001) 4.03-fold increase in tumor tissue, giving further insights into the roles of macrophages and tumor cells in supporting the immunosuppressive TME. Multivariate Cox proportional hazards models investigating the interaction of TGFB2 and activation of IFNGR2, STAT1, IRF1, or IRF5 showed that the prognostic impact of high mRNA levels (25th percentile cut-off) of TGFB2 was independent of IFNGR2, STAT1, IRF1, or IRF5 mRNA levels (TGFB2high HR (95% CI) = 4.07 (2.35–7.06), 6 (3.62–10.11), 4.38 (2.67–7.17), and 4.48 (2.82–7.12) for models with IFNGR2, STAT1, IRF1, or IRF5, respectively) and age at diagnosis. Patients with high levels of TGFB2 and IFNGR2 were over-represented by LGG patients with isocitrate dehydrogenase wild-type (IDHwt) mutation status. The prognostic impact of high levels of TGFB2 and IDH wild-type observed by the increases in hazard ratios for TGFB2 (HR (95% CI range) = 2.02 (1.05–3.89)) and IDH wild-type (HR (95% CI range) = 4.44 (1.9–10.4)) were independent predictors of survival, suggesting that risk stratification of patients identifies LGG patients with IDH wild-type and high levels of TGFB2 in the design of clinical trials. Furthermore, we have additional IRF5 and CD276/B7-H3 as prognostic markers that can also be targeted for combination therapies with TGFB2 inhibitors. In support of these findings, we demonstrated that low levels of gene methylation in TGFB2, IFNGR2, IRF1, IRF5, STAT1, and CD276 were associated with significantly worse overall survival (OS) outcomes. This suggests that potential mechanisms to increase the expression of these prognostic markers occur via the action of demethylation enzymes.

show abstract

“…Kinetics of the early innate immune activation during HIV-1 infection of humanized mice have further shed light on the complexity of the interaction with the IFN system during the infectionʹs eclipse, burst, and chronic phase [46]. More details about the IFN system are available from others [14,17,24,[47][48][49][50][51][52][53].…”

Section: Coronavirus Replicationmentioning

confidence: 99%

SARS-CoV-2 Evasion of the Interferon System: Can We Restore Its Effectiveness?

Sacchi

Giannessi

Sabatini

et al. 2023

IJMS

View full text Add to dashboard Cite

Type I and III Interferons (IFNs) are the first lines of defense in microbial infections. They critically block early animal virus infection, replication, spread, and tropism to promote the adaptive immune response. Type I IFNs induce a systemic response that impacts nearly every cell in the host, while type III IFNs’ susceptibility is restricted to anatomic barriers and selected immune cells. Both IFN types are critical cytokines for the antiviral response against epithelium-tropic viruses being effectors of innate immunity and regulators of the development of the adaptive immune response. Indeed, the innate antiviral immune response is essential to limit virus replication at the early stages of infection, thus reducing viral spread and pathogenesis. However, many animal viruses have evolved strategies to evade the antiviral immune response. The Coronaviridae are viruses with the largest genome among the RNA viruses. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic. The virus has evolved numerous strategies to contrast the IFN system immunity. We intend to describe the virus-mediated evasion of the IFN responses by going through the main phases: First, the molecular mechanisms involved; second, the role of the genetic background of IFN production during SARS-CoV-2 infection; and third, the potential novel approaches to contrast viral pathogenesis by restoring endogenous type I and III IFNs production and sensitivity at the sites of infection.

show abstract

A structural “star” in interferon gamma signaling

Cited by 4 publications

References 16 publications

Transforming Growth Factor Beta 2 (TGFB2) and Interferon Gamma Receptor 2 (IFNGR2) mRNA Levels in the Brainstem Tumor Microenvironment (TME) Significantly Impact Overall Survival in Pediatric DMG Patients

Transforming Growth Factor Beta 2 (TGFB2) and Interferon Gamma Receptor 2 (IFNGR2) mRNA Levels in the Brainstem Tumor Microenvironment (TME) Significantly Impact Overall Survival in Pediatric DMG Patients

Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas

SARS-CoV-2 Evasion of the Interferon System: Can We Restore Its Effectiveness?

Contact Info

Product

Resources

About