Interferon Regulatory Factor 4 Regulates the Development of Polymorphonuclear Myeloid-Derived Suppressor Cells Through the Transcription of c-Myc in Cancer

Yang, Quan; Xie, Hongyan; Li, Xing; Feng, Yuanfa; Xie, Shihao; Qu, Jiale; Xie, Anqi; Zhu, Yuemin; Zhou, Lu; Yang, Jinxue; Hu, Xiaohao; Wei, Haixia; Qiu, Huaina; Qin, Wenjuan; Huang, Jun

doi:10.3389/fimmu.2021.627072

Cited by 10 publications

(6 citation statements)

References 43 publications

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“…IRF4 was overexpressed and activated the cancer progression by Notch signaling pathway in human non-small-cell lung cancer [ 37 ]. IRF4 might be a novel regulator of PMN-MDSC development in cancer [ 38 ]. The miR-320/IRF6 signaling axis played an important role in pulmonary canceration [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

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A Comprehensive Analysis of Interferon Regulatory Factor Expression: Correlation with Immune Cell Infiltration and Patient Prognosis in Endometrial Carcinoma

Ying

et al. 2022

BioMed Research International

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As a family of transcription factors, the correlations between expression pattern of nine interferon regulatory factor (IRF) family members, the immune invasion pattern, and the associated patient survival rate in endometrial carcinoma (EC) remain to be elucidated. Based on The Cancer Genome Atlas (TCGA), the expression profiles of the high and low IRF mRNA expression groups were analyzed using R (3.6.3) statistical software. Gene annotation and pathway analyses were performed using Metascape. GSEA was performed using the R package clusterProfiler (3.6.3). The single-sample gene set enrichment analysis (ssGSEA) was used to quantify the relative tumor infiltration levels of immune cell types. Immunohistochemistry data provided by HPA database was used to study the expression of the IRF proteins. Using the GEPIA dataset, the correlation between the expression of IRFs and the tumor stage of EC was analyzed. The correlations between the different IRFs were analyzed using cBioPortal. The expression of IRF2, IRF3, IRF5, IRF6, IRF7, IRF8, and IRF9 was different when comparing EC and normal endometrial samples. IRF2, IRF6, IRF7, and IRF8 were indicated to be potential diagnostic markers for EC. In combination with receiver operating characteristic analysis results, IRF2, IRF6, IRF7, and IRF8 were indicated to be potential diagnostic markers for EC. Levels of individual IRFs were associated with alternate outcomes, with the expression of IRF3 being correlated with the stage of EC and high expression of IRF4 being positively correlated with overall survival (OS); conversely, high expression of IRF5 was negatively correlated with OS. Additionally, high expression levels of both IRF2 and IRF4 were positively correlated with the disease-specific survival rate, and high expression of IRF4 was positively correlated with the progression-free interval. These data suggest a role for IRF2, IRF4, and IRF5 in the prognosis of EC. The expression of IRFs is associated with immune infiltration.

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Section: Discussionmentioning

confidence: 99%

“…IRFs show an imbalance expression and played different roles in the occurrence and development of in many different cancers [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. IRF6 might enhance chemotherapeutic sensitivity of cisplatin in colorectal cancer [36].…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Analysis of Interferon Regulatory Factor Expression: Correlation with Immune Cell Infiltration and Patient Prognosis in Endometrial Carcinoma

Ying

et al. 2022

BioMed Research International

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“…The oncogene proteins expressed by tumor cells stimulate and induce the abnormal activation of effector T cells (1,2). Multiple soluble tumor-derived products, such as the chemokines CCL2, CCL5 and the cytokines IL10 and TGFb, etc., recruit tumor-associated macrophages (TAMs) (3)(4)(5)(6) and myeloid-derived suppressor cells (MDSCs) (7) into the TME, and lead to the impairment of differentiation, maturation and function of dendritic cells (DCs) (8,9). These factors in turn jointly aggravates TME disorders, inhibits the anti-tumor immunity of effector T cells, and induces T cell exhaustion and the development of regulatory T (Treg) cells (2).…”

Section: Introductionmentioning

confidence: 99%

“…In parallel, IRF4 is also involved in T cell exhaustion in specific biological contexts ( 24 , 25 ). In contrast, it plays an important role in the differentiation and function of various immunosuppressive cells, such as Th2 cells, Treg cells, TAMs and MDSCs, establishing an immunosuppressive TME to inhibit anti-tumor immunity and favor the immune escape and survival of tumor cells ( 3 – 5 , 7 ) ( Figure 1 ). Thus, an in-depth understanding of the effects and potential mechanisms of IRF4 in a variety of immune cells and a disordered TME may provide new directions for clinical immune intervention.…”

Section: Introductionmentioning

confidence: 99%

Regulatory effects of IRF4 on immune cells in the tumor microenvironment

Liang²,

Li³

et al. 2023

Front. Immunol.

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The tumor microenvironment (TME) is implicated in tumorigenesis, chemoresistance, immunotherapy failure and tumor recurrence. Multiple immunosuppressive cells and soluble secreted cytokines together drive and accelerate TME disorders, T cell immunodeficiency and tumor growth. Thus, it is essential to comprehensively understand the TME status, immune cells involved and key transcriptional factors, and extend this knowledge to therapies that target dysfunctional T cells in the TME. Interferon regulatory factor 4 (IRF4) is a unique IRF family member that is not regulated by interferons, instead, is mainly induced upon T-cell receptor signaling, Toll-like receptors and tumor necrosis factor receptors. IRF4 is largely restricted to immune cells and plays critical roles in the differentiation and function of effector cells and immunosuppressive cells, particularly during clonal expansion and the effector function of T cells. However, in a specific biological context, it is also involved in the transcriptional process of T cell exhaustion with its binding partners. Given the multiple effects of IRF4 on immune cells, especially T cells, manipulating IRF4 may be an important therapeutic target for reversing T cell exhaustion and TME disorders, thus promoting anti-tumor immunity. This study reviews the regulatory effects of IRF4 on various immune cells in the TME, and reveals its potential mechanisms, providing a novel direction for clinical immune intervention.

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“…Furthermore, in the pre-tyrosine kinase inhibitors (TKI) era, a significant increase in IRF4 expression levels was detected in chronic myeloid leukemia (CML) patients during interferon-alpha (IFN-a) therapy, and a good response to treatment was associated with higher IRF4 levels [4]. Its involvement in the homeostasis of both inflammation (i.e., through the polarization of macrophages) and immune surveillance (i.e., through the modulation of MD-SCs) has fueled interest in investigating potential IRF4 implications in both the pathogenesis and clinical course of MPNs [5,6]. Notably, a growing body of evidence demonstrates that these neoplasms are characterized by chronic inflammation, contributing to the pathogenesis of the disease [7,8].…”

Section: Introductionmentioning

confidence: 99%

IRF4 Gene Expression on the Trail of Molecular Response: Looking at Chronic Myeloid Leukemia from Another Perspective

et al. 2022

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Introduction Interferon regulatory factor 4 (IRF4) is a transcriptional factor with a key role in the modulation of inflammation and immune surveillance. The IRF4 gene is downregulated in Philadelphia-negative myeloproliferative neoplasms, and its expression is associated with prognosis and response to treatment. Methods We evaluated the IRF4 expression kinetics during tyrosine kinase inhibitor (TKI) treatment in a cohort of 116 chronic myeloid leukemia (CML) patients to elucidate its role in the disease course. Results A relationship between the IRF4 expression and the disease burden was observed at various disease stages. A correlation analysis between the International Scale (IS) and IRF4 values confirmed this close association. A significant increase is detected after 3 months of TKI treatment. Patients achieving early molecular response (EMR) had higher IRF4 values at both diagnosis and after 3 months of therapy as compared to those failing the EMR target. Patients achieving treatment-free remission (TFR) did not show IRF4 fluctuations during monitoring, while a decreased IRF4 expression emerged at the time of molecular relapse. Conclusion Our data seem to confirm the relevance of IRF4 in the pathogenesis of CML, suggesting a pivotal role at the disease onset and a predictive value during the CML course.

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Interferon Regulatory Factor 4 Regulates the Development of Polymorphonuclear Myeloid-Derived Suppressor Cells Through the Transcription of c-Myc in Cancer

Cited by 10 publications

References 43 publications

A Comprehensive Analysis of Interferon Regulatory Factor Expression: Correlation with Immune Cell Infiltration and Patient Prognosis in Endometrial Carcinoma

A Comprehensive Analysis of Interferon Regulatory Factor Expression: Correlation with Immune Cell Infiltration and Patient Prognosis in Endometrial Carcinoma

Regulatory effects of IRF4 on immune cells in the tumor microenvironment

IRF4 Gene Expression on the Trail of Molecular Response: Looking at Chronic Myeloid Leukemia from Another Perspective

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