IRF4 instructs effector Treg differentiation and immune suppression in human cancer

Alvisi, Giorgia; Brummelman, Jolanda; Puccio, Simone; Mazza, Emilia Maria Cristina; Tomada, Elisa Paoluzzi; Losurdo, Agnese; Zanon, Veronica; Peano, Clelia; Colombo, Federico; Scarpa, Alice; Alloisio, Marco; Vasanthakumar, Ajithkumar; Roychoudhuri, Rahul; Kallikourdis, Marinos; Pagani, Massimiliano; Lopci, Egesta; Novellis, Pierluigi; Blume, Jonas; Kallies, Axel; Veronesi, Giulia; Lugli, Enrico

doi:10.1172/jci130426

Cited by 119 publications

(143 citation statements)

References 73 publications

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“…The insulin-like growth factor 1(IGF1) pathway has been proven to contribute to the suppression of immune tumor microenvironment(TME) in gynecologic cancers [44]. IRF4 + Tregs have been con rmed to be correlated with poor prognosis in patients with multiple cancers [45]. NFATC2 regulates IL-21 expression in human CD4 + CD45RO + T lymphocytes [46].STAT6 is a factor converge on intracellular determinants of cell functions and drives the recruitment and polarization of tumor-associated macrophages (TAMs) [47].…”

Section: Discussionmentioning

confidence: 99%

Immune‐related Long Noncoding RNA Signature for Patients with Cervical Cancer

Zheng

Tong

Cao

et al. 2020

Preprint

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Background: Cervical cancer (CC) is a common gynecological malignancy for which prognostic and therapeutic biomarkers are urgently needed. The signature based on immune‐related lncRNAs(IRLs) of CC has never been reported. This study aimed to establish an IRL signature for patients with CC.Methods: The RNA-seq dataset was obtained from the TCGA, GEO, and GTEx database. The immune scores（IS）based on single-sample gene set enrichment analysis (ssGSEA) were calculated to identify the IRLs, which were then analyzed using univariate Cox regression analysis to identify significant prognostic IRLs. A risk score model was established to divide patients into low-risk and high-risk groups based on the median risk score of these IRLs. This was then validated by splitting TCGA dataset(n=304) into a training-set(n=152) and a valid-set(n=152). The fraction of 22 immune cell subpopulations was evaluated in each sample to identify the differences between low-risk and high-risk groups. Additionally, a ceRNA network associated with the IRLs was constructed.Results: A cohort of 326 CC and 21 normal tissue samples with corresponding clinical information was included in this study. Twenty-eight IRLs were collected according to the Pearson’s correlation analysis between immune score and lncRNA expression (P < 0.01). Four IRLs (BZRAP1-AS1, EMX2OS, ZNF667-AS1, and CTC-429P9.1) with the most significant prognostic values (P < 0.05) were identified which demonstrated an ability to stratify patients into low-risk and high-risk groups by developing a risk score model. It was observed that patients in the low‐risk group showed longer overall survival (OS) than those in the high‐risk group in the training-set, valid-set, and total-set. The area under the curve (AUC) of the receiver operating characteristic curve (ROC curve) for the four IRLs signature in predicting the one-, two-, and three-year survival rates were larger than 0.65. In addition, the low-risk and high-risk groups displayed different immune statuses in GSEA. These IRLs were also significantly correlated with immune cell infiltration. Conclusions: Our results showed that the IRL signature had a prognostic value for CC. Meanwhile, the specific mechanisms of the four-IRLs in the development of CC were ascertained preliminarily.

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Section: Discussionmentioning

confidence: 99%

Immune‐related Long Noncoding RNA Signature for Patients with Cervical Cancer

Zheng

Tong

Cao

et al. 2020

Preprint

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“…Indeed, conditional ablation of Irf4 in Treg cells leads to a multifocal and lethal autoimmune disease [38]. More recently, it was shown that IRF4 expression also defines the activated subset of tumor-infiltrating Treg cells in patients with lung cancer and may even regulate the human aTreg phenotype [39]. Furthermore, this tumor-promoting function was demonstrated in mice with tamoxifen-induced ablation of Irf4 in Treg cells, which display reduced growth of transplanted colon adenocarcinoma [39].…”

Section: Irf4mentioning

confidence: 99%

“…More recently, it was shown that IRF4 expression also defines the activated subset of tumor-infiltrating Treg cells in patients with lung cancer and may even regulate the human aTreg phenotype [39]. Furthermore, this tumor-promoting function was demonstrated in mice with tamoxifen-induced ablation of Irf4 in Treg cells, which display reduced growth of transplanted colon adenocarcinoma [39]. Because IRF4 may also promote T conv cell exhaustion [40], it is emerging as a promising target in cancer.…”

Section: Irf4mentioning

confidence: 99%

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

Stéphan¹,

Lautraite²,

Voisin³

et al. 2020

Cancers

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Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators.

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“…Moreover, BCL6 takes part in the inflammatory activity and differentiation of Th2 cells [ 16 , 17 ]. In addition, IRF4 plays a role in the regulation of Treg differentiation in human cancer [ 18 ]. IRF4 regulates the immunosuppressive function of Tregs in primary immune thrombocytopenia [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

IRF4 overexpression promotes the transdifferentiation of tregs into macrophage‐like cells to inhibit the development of colon cancer

Wang

Song

et al. 2021

Cancer Cell Int

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Background Interferon regulatory factor 4 (IRF4) is a transcription factor from the IRF factor family that exerts regulatory functions in the immune system and oncogenesis. However, the biological role of IRF4 in colon cancer is still unclear. The aim of this study is to investigate whether IRF4 participates in the immune response in colon cancer. Methods We compared the expression of IRF4, the number of regulatory T cells (Tregs) and macrophages in the colon cancer tissues and paracancerous colon tissues from colon cancer patients. Colon cancer mouse model was established by inoculation with colon cancer cells (SW480) as a xenograft tumor, and we observed tumor growth of colon cancer. Furthermore, the mechanism of action of IRF4 in transdifferentiation of Tregs into macrophage-like cells and the effect of IRF4 on colon cancer cells were investigated in vitro. Results IRF4 was severely down-regulated in the colon cancer tissues. Colon cancer tissues exhibited an increase in the number of regulatory T cells (Tregs) and macrophages. Furthermore, IRF4 overexpression repressed proliferation, migration and invasion of colon cancer cells (SW480 and HT116 cells). Moreover, IRF4 up-regulation ameliorated tumor growth of colon cancer by promoting the transdifferentiation of Tregs into macrophage-like cells through inhibition of BCL6 expression. Exosomes derived from colon cancer cells repressed IRF4 expression in Tregs by transmitting miR-27a-3p, miR-30a-5p and miR-320c. Conclusions IRF4 overexpression promoted the transdifferentiation of Tregs into macrophage-like cells to inhibit the occurrence and development of colon cancer. Thus, IRF4 may be a potential target for colon cancer treatment.

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IRF4 instructs effector Treg differentiation and immune suppression in human cancer

Cited by 119 publications

References 73 publications

Immune‐related Long Noncoding RNA Signature for Patients with Cervical Cancer

Immune‐related Long Noncoding RNA Signature for Patients with Cervical Cancer

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

IRF4 overexpression promotes the transdifferentiation of tregs into macrophage‐like cells to inhibit the development of colon cancer

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