FOXP3

Gene Summary

Gene:FOXP3; forkhead box P3
Aliases: JM2, AIID, IPEX, PIDX, XPID, DIETER
Location:Xp11.23
Summary:The protein encoded by this gene is a member of the forkhead/winged-helix family of transcriptional regulators. Defects in this gene are the cause of immunodeficiency polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), also known as X-linked autoimmunity-immunodeficiency syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:forkhead box protein P3
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
Show (82)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cancer Gene Expression Regulation
  • Single Nucleotide Polymorphism
  • T-Lymphocytes
  • Melanoma
  • Biomarkers, Tumor
  • Mutation
  • Polymorphism
  • Single-Stranded Conformational Polymorphism
  • RTPCR
  • Vocal Cords
  • beta 2-Microglobulin
  • Tumor Suppressor Proteins
  • Colorectal Cancer
  • CD4-Positive T-Lymphocytes
  • Forkhead Transcription Factors
  • Up-Regulation
  • Lymphocytes, Tumor-Infiltrating
  • Republic of Korea
  • Estrogen Receptors
  • X Chromosome Inactivation
  • Precision Medicine
  • Immunohistochemistry
  • Flow Cytometry
  • Phenotype
  • Skin Cancer
  • Receptor, erbB-2
  • FOXP3
  • Tryptophan
  • Serum Albumin
  • Gene Expression
  • Prostate Cancer
  • T-Lymphocytes, Regulatory
  • Promoter Regions
  • Breast Cancer
  • Messenger RNA
  • Interleukin-17
  • Adenocarcinoma
  • X Chromosome
  • CD8-Positive T-Lymphocytes
  • Cell Proliferation
  • CD Antigens
  • Staging
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FOXP3 (cancer-related)

Sanmartín E, Ortiz-Martínez F, Pomares-Navarro E, et al.
CD44 induces FOXP3 expression and is related with favorable outcome in breast carcinoma.
Virchows Arch. 2017; 470(1):81-90 [PubMed] Related Publications
We studied the relationship between CD44 and Forkhead box P3 (FOXP3) gene expression in cell lines and breast carcinomas and their association with clinicopathological variables and patient outcome. We assessed messenger RNA (mRNA) expression of CD44 and FOXP3 by quantitative real-time PCR and determined the number of FOXP3+ Tregs by immunohistochemistry in 264 breast cancer specimens. CD44 was stimulated with hyaluronan treatment, and the accompanying changes in FOXP3 mRNA expression in breast cancer cell lines representing breast cancer subtype were assessed. We found that lower CD44 expression correlated with the presence of necrosis, lymph-vascular invasion, grade 3 tumors, and aggressive phenotype (HER2 and basal-like). FOXP3 mRNA correlated positively with CD44 mRNA expression and Treg content. Moreover, stimulation of CD44 expression by hyaluronan in cell lines increased FOXP3 expression, which supports that their regulation is associated. Survival analysis revealed that low CD44 expression is associated with higher frequency of recurrence. Our findings indicate that CD44 has a regulatory role in FOXP3 expression and is associated with good prognostic factors in breast cancer.

Sun Z, Zhang B, Wang C, et al.
Forkhead box P3 regulates ARHGAP15 expression and affects migration of glioma cells through the Rac1 signaling pathway.
Cancer Sci. 2017; 108(1):61-72 [PubMed] Free Access to Full Article Related Publications
Forkhead box P3 (FOXP3) plays a crucial role in the development and function of regulatory T cells and was recently identified as a tumor suppressor in different cancer types. Forkhead box P3 is expressed in normal brain tissues, but is strongly downregulated or absent in glioblastomas. In order to understand the FOXP3 adjustment mechanisms in glioma cells, we performed a DNA microarray in U87 cells overexpressing FOXP3 and validated the differences using quantitative real-time PCR, Western blot analysis, and immunohistochemistry in vitro and in vivo. We found that FOXP3 can regulate the expression of ARHGAP15. Expression of FOXP3 was also correlated with ARHGAP15 in glioma samples. Overexpression of FOXP3 inhibited glioma cell migration through ARHGAP15 upregulation and Rac1 inactivation. Silencing of FOXP3 promoted migration through ARHGAP15 downregulation and Rac1 activation. ARHGAP15, a GTPase-activating protein for Rac1, inhibits small GTPase signaling in a dual negative manner. We found that there is a correlation between expression of ARHGAP15 and glioma level. The small GTPase Rac1 plays an important role in cell migration. In addition, we found that FOXP3 regulates expression of epithelial-mesenchymal transition markers E-cadherin and N-cadherin, which is important given that epithelial-mesenchymal transition is critically involved in tumor spreading and dissemination. Thus, FOXP3 or ARHGAP15 may serve as a new molecular target for antimetastatic therapies in treating glioma.

Payne KK
Lymphocyte-mediated Immune Regulation in Health and Disease: The Treg and γδ T Cell Co-conspiracy.
Immunol Invest. 2016; 45(8):767-775 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
The significance of lymphocytes functioning to mediate immunological tolerance has garnered increasing appreciation during the last several decades. CD4+ CD25+ α/ β T cells have arguably been the most extensively studied regulatory lymphocyte to date, perhaps owing to the dramatic phenotype observed mice and humans with mutated Foxp3. However, emerging studies suggest that the lineage of regulatory lymphocytes is quite robust. Most notably, while γδ T cells are more traditionally regarded as mediators of cytotoxic function, they are beginning to be regarded as potential negative regulators of immunity. While regulatory γ/δ T cells may possess a degree of transcriptional overlap with 'classical Tregs', there remains less clarity in regard to the mechanisms driving the suppressive potential of these cells. In this review, I will discuss the role of Tregs in establishing tolerance in the steady state as well as disease, and how their accumulation and function may be modulated by myeloid cells in the local microenvironment. I will also discuss the necessity to extend our understanding of the regulatory nature of γδ T cells, which may lead to the unearthing of novel paradigms of immunity, perhaps most notably with respect to cancer.

Manjili MH, Butler SE
Role of Tregs in Cancer Dormancy or Recurrence.
Immunol Invest. 2016; 45(8):759-766 [PubMed] Related Publications
The immunogenic tumor dormancy has been demonstrated in animal models of cancer, which can explain clinical observations such as an increased incidence of cancer following organ transplantation. The role of immune cell populations in the maintenance of, or escape from, tumor dormancy and subsequent recurrence is poorly understood. Here, we provide a review of literature related to the contribution of Tregs in tumor dormancy or recurrence. Based on clinical results, we suggest that anecdotal reports on the association of human Tregs with poor prognosis are circumstantial rather than implying a cause-effect direction. This could be due to a disparity among patients in harboring multiple factors associated with tumor immunoediting and immune evasion mechanisms.

Singh M, Loftus T, Webb E, Benencia F
Minireview: Regulatory T Cells and Ovarian Cancer.
Immunol Invest. 2016; 45(8):712-720 [PubMed] Related Publications
In the last 15 years, it has become apparent that ovarian cancer is recognized by the immune system, taking into account that T cell infiltration can be associated with increased overall survival. Several studies indicate that a correct combination of cluster of differentiation 8 and cluster of differentiation 4 T cells is key to fight tumor progression and that the presence of regulatory T cells (Tregs) infiltrating ovarian solid tumors (or present in ascites) is deleterious. Several markers that characterize Tregs include glucocorticoid-induced tumor necrosis factor receptor, cytotoxic T lymphocyte antigen-4, and forkhead box protein 3 (Foxp3). Research has shown that Tregs can infiltrate cancerous tissue and contribute to tumor growth by secreting immunosuppressive cytokines such as transforming growth factor beta and interleukin (IL)-10. Importantly, these cells might hamper the efficacy of immunotherapeutic approaches, thus strategies involving depletion or regulation of this population have been proposed and tested in experimental models. In this Minireview, we will discuss the relevance of Tregs in ovarian cancer and the experimental approaches destined to impair their immunosuppressive effects.

Liu G, Luan J, Li Q
CD4(+)Foxp3(-)IL-10(+) Tr1 Cells Promote Relapse of Diffuse Large B Cell Lymphoma by Enhancing the Survival of Malignant B Cells and Suppressing Antitumor T Cell Immunity.
DNA Cell Biol. 2016; 35(12):845-852 [PubMed] Related Publications
Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy. Complete remission can be achieved in most patients by conventional treatment with rituximab and chemotherapy. However, a subset of remission individuals will develop a relapsed disease for obscure reasons. CD4(+)Foxp3(-)IL-10(+) cell (Tr1) is a novel cell subtype with the capacity to suppress pro-inflammatory responses, but has not been extensively studied in most tumors. In this study, we investigated the potential role of Tr1 cells in DLBCL. We found that compared to that in healthy controls, the frequency of Tr1 cells was significantly increased in DLBCL patients, even during complete remission. Further study showed that these Tr1 cells were enriched in the CD25(low/-)Foxp3(-)CD49b(+)LAG-3(+) fraction and could be developed in vitro from naive CD45RA(+) CD4(+) T cells. To examine the effect of Tr1 upregulation, we cocultured the enriched in vitro-induced Tr1 cells (iTr1) with autologous primary DLBCL cells and CD3(+) T cells and found that iTr1 cells both enhanced the survival of CD20(+) DLBCL tumor cells and suppressed the antitumor response of CD3(+) T cells through the production of IL-10. Furthermore, the frequency of CD4(+)Foxp3(-)IL-10(+) Tr1 cells in DLBCL patients during complete remission is directly associated with the risk of relapse. Together, these results suggested that Tr1 cells contributed to tumor cell maintenance and may serve as a prognostic marker and therapeutic target.

Wang X, Liu Y, Dai L, et al.
Foxp3 downregulation in NSCLC mediates epithelial-mesenchymal transition via NF-κB signaling.
Oncol Rep. 2016; 36(4):2282-8 [PubMed] Related Publications
Forkhead box P3 (Foxp3) is a member of forkhead box transcription factor family and it was identified as a tumor suppressor in various solid tumors. This study evaluated the expression of Foxp3 in non-small cell lung cancer (NSCLC) and investigated its role in epithelial‑mesenchymal transition (EMT) of cancer cells. qRT-PCR and western blot analysis were used for examining the expression of Foxp3 in NSCLC tissues and the non-tumor tissues. A tissue microarray was constructed and scored for evaluating the clinical significance of Foxp3 expression in NSCLC tissues. RNAi was employed for downregulating Foxp3 expression and cell proliferation was done with MTT assay. Transwell with or without basement membrane matrix was used for cell migration and invasion assay respectively. Foxp3 was found downregulated in NSCLC tissues compared with non-tumoral tissues; downregulation of Foxp3 predicted adverse tumor stage and overall survival; silencing of FOXP3 promoted the proliferation, migration and invasion ability of NSCLC cells and influenced the expression level of EMT-associated proteins. However, forced expression of Foxp3 could reverse this effect. Moreover, Foxp3 could interact with LMO2 and affect the expression level of TAL1, which was in accordance with the findings in T-cell acute lymphoblastic leukemia. By screening the signalling pathways, we observed an obvious upregulation of phosphorylated NF-κB in A549 and H520 cells after silencing of FOXP3. Our results suggest that Foxp3 suppressed NSCLC cell metastasis, at least partially, via NF-κB signaling.

Szylberg Ł, Karbownik D, Marszałek A
The Role of FOXP3 in Human Cancers.
Anticancer Res. 2016; 36(8):3789-94 [PubMed] Related Publications
FOXP3 transcription factor can be observed as the main component of the immune system expressed in regulatory T (Treg) cells that regulate hemostasis and self-tolerance. Moreover, the altered expression of FOXP3 was found in autoimmune diseases, benign tumors and carcinomas. Latest reports indicate that the FOXP3 gene mutation can contribute to carcinogenesis, which can be associated with immune response abnormalities. Infiltration of the Treg cells into tumor cells can be associated with prognosis. Understanding the biology of the FOXP3 gene may be crucial in developing new immunotherapeutics.

Tian W, Wang L, Yuan L, et al.
A prognostic risk model for patients with triple negative breast cancer based on stromal natural killer cells, tumor-associated macrophages and growth-arrest specific protein 6.
Cancer Sci. 2016; 107(7):882-9 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
The aim of this study was to establish a prognostic risk model for patients with triple negative breast cancer (TNBC). A total of 278 specimens of human TNBC tissues were investigated by immunohistochemistry for growth-arrest specific protein 6 expression, infiltrations of stromal natural killer cells and tumor-associated macrophages. According to their prognostic risk scores based on the model, patients were divided into three groups (score 0, 1-2, 3). Correlations of prognostic risk scores, clinicopathologic features and overall survival (OS) were analyzed. To study the clinical value of this stratification model in early disease recurrence or metastasis, 177 patients were screened out for further analysis. Based on disease free survival (DFS), 90 patients fell within the DFS ≤3 years group and 87 patients within the DFS ≥5 years group. We analyzed the differences in prognostic risk scores between the two groups. The prognostic risk scores were negatively related to tumor size, lymph node metastasis and P53 status (P < 0.001 for all). Patients with low prognostic risk scores had longer OS (P = 0.001). Using multivariate analysis, it was determined that TNM stage (HR = 0.432, 95% confidence interval [CI] = 0.281-0.665, P = 0.003), FOXP3 positive lymphocytes (HR = 1.712, 95% CI = 1.085-2.702, P = 0.021) and prognostic risk scores (HR = 1.340, 95% CI = 1.192-1.644, P = 0.005) were independent prognostic factors for OS. Compared with the DFS ≥5 years group, the DFS ≤3 years group patients had significantly higher prognostic risk scores (P < 0.001). In conclusion, the prognostic risk score of the model was a significant indicator of prognosis for patients with TNBC.

Wang XT, Lv M, Guo HY
Effects of epidural block combined with general anesthesia on antitumor characteristics of T helper cells in hepatocellular carcinoma patients.
J Biol Regul Homeost Agents. 2016 Jan-Mar; 30(1):67-77 [PubMed] Related Publications
This study discusses the changes of T helper cells (Th cells) of patients who received different anesthesia methods in liver cancer resection. We selected 122 patients who were diagnosed with hepatocellular carcinoma and underwent liver cancer resection and divided them into a general anesthesia combined with epidural anesthesia group (group A) and general anesthesia group (group B). Peripheral blood was collected to detect Th cells on the day of surgery, and on the second and seventh days after surgery. Th1 and Th2 cell frequency and mRNA expression of interferon-γ (IFN-γ) of all patients significantly rose on the second day but recovered to the previous level on the seventh day. Th1/Th2 increased remarkably on the seventh day compared to the second day. Compared to the day of surgery, Th17, regulatory T (Treg)cells as well as mRNA expression of interleukin-17 (IL-17) and FoxP3 had no obvious changes on the second day, but dramatically declined on the seventh day. Compared to group B, Th1 cell frequency and Th1/Th2 in group A had a slight increase on the second day, and a remarkable increase on the seventh day; but Th2, Th17 and Treg cell frequency in group A slightly decreased on the second day and remarkably decreased on the seventh day. mRNA of IFN-γ, cytokine levels and IFN-γ/IL-4 of group A were all higher than group B on the seventh day, while mRNA of IL-17, concentration of IL-17 as well as concentration of transforming growth factor-β1 (TGF-β1) in group A were much lower than group B. These findings suggest that improving antitumor activity of Th cells can benefit patients who receive liver cancer resection.

Zheng Y, Shao X, Huang Y, et al.
Role of estrogen receptor in breast cancer cell gene expression.
Mol Med Rep. 2016; 13(5):4046-50 [PubMed] Related Publications
The aim of the present study was to establish the underlying regulatory mechanism of estrogen receptor (ER) in breast cancer cell gene expression. A gene expression profile (accession no. GSE11324) was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) from an estrogen treatment group and a control group were identified. Chromatin immunoprecipitation with high‑throughput sequencing data (series GSE25710) was obtained from the GEO for the ER binding sites, and binding and expression target analysis was performed. A total of 3,122 DEGs were obtained and ER was demonstrated to exhibit inhibition and activation roles during the regulation of its target gene expression. Motif analysis revealed that the upregulated target genes that demonstrated interactions with ER were meis homeobox 1 (MEIS1) and forkhead box P3 (FOXP3). The downregulated target genes, which demonstrated interactions with ER, were thyroid hormone receptor, β (THRB) and grainyhead‑like 1 (GRHL1). Thus, it was observed that ER stimulated gene expression by interacting with MEIS1 and FOXP3, and ER inhibited gene expression by interacting with THRB and GRHL1. However, additional experiments are required to provide further confirmation of these findings.

Ke X, Zhang S, Xu J, et al.
Non-small-cell lung cancer-induced immunosuppression by increased human regulatory T cells via Foxp3 promoter demethylation.
Cancer Immunol Immunother. 2016; 65(5):587-99 [PubMed] Related Publications
Patients with non-small-cell lung cancer (NSCLC) have immune defects that are poorly understood. Forkhead box protein P3 (Foxp3) is crucial for immunosuppression by CD4(+) regulatory T cells (Tregs). It is not well known how NSCLC induces Foxp3 expression and causes immunosuppression in tumor-bearing patients. Our study found a higher percentage of CD4(+) Tregs in the peripheral blood of NSCLC compared with healthy donors. NSCLC patients showed demethylation of eight CpG sites within the Foxp3 promoter with methylation ratios negatively correlated with CD4(+)CD25(+)Foxp3(+) T levels. Foxp3 expression in CD4(+) Tregs was directly regulated by Foxp3 promoter demethylation and was involved in immunosuppression by NSCLC. To verify the effect of tumor cells on the phenotype and function of CD4(+) Tregs, we established a coculture system using NSCLC cell line and healthy CD4(+) T cells and showed that SPC-A1 induced IL-10 and TGF-β1 secretion by affecting the function of CD4(+) Tregs. The activity of DNA methyltransferases from CD4(+) T was decreased during this process. Furthermore, eight CpG sites within the Foxp3 promoter also appeared to have undergone demethylation. Foxp3 is highly expressed in CD4(+) T cells, and this may be caused by gene promoter demethylation. These induced Tregs are highly immunosuppressive and dramatically inhibit the proliferative activity of naïve CD4(+) T cells. Our study provides one possible mechanism describing Foxp3 promoter demethylation changes by which NSCLC down-regulates immune responses and contributes to tumor progression. Foxp3 represents an important target for NSCLC anti-tumor immunotherapy.

Shen L, Orillion A, Pili R
Histone deacetylase inhibitors as immunomodulators in cancer therapeutics.
Epigenomics. 2016; 8(3):415-28 [PubMed] Related Publications
HDAC inhibitors (HDACIs) are anticancer agents being developed in preclinical and clinical settings due to their capacity to modulate gene expression involved in cell growth, differentiation and apoptosis, through modification of both chromatin histone and nonhistone proteins. Most HDACIs in clinical development have cytotoxic or cytostatic properties and their direct inhibitory effects on tumor cells are well documented. Numerous studies have revealed that HDACIs have potent immunomodulatory activity in tumor-bearing animals and cancer patients, providing guidance to apply these agents in cancer immunotherapies. Here, we summarize recent reports addressing the effects of HDACIs on tumor cell immunogenicity, and on different components of the host immune system. In addition, we discuss the complexity of the immunomodulatory activity of these agents, which depends on the class specificity of the HDACIs, different experimental settings and the target immune cell populations.

Kawaguchi K, Suzuki E, Yamaguchi A, et al.
Altered expression of major immune regulatory molecules in peripheral blood immune cells associated with breast cancer.
Breast Cancer. 2017; 24(1):111-120 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND: The purpose of this study was to clarify the alterations of major immune regulators in peripheral blood mononuclear cells (PBMCs) of cancer patients and to analyze the association with the disease progression in breast cancer patients.
METHODS: The study included 6 healthy volunteers (HVs), 12 primary breast cancer (PBC) patients, and 30 metastatic breast cancer (MBC) patients. The expression of immune regulators such as, CCR6, CD4, CD8, CD14, CD40, CD56, CD80, CTLA4, CXCR4, FOXP3, IDO-1, IDO-2, NKG2D, NRP-1, PD-1, and PD-L1 mRNA in PBMCs was measured by quantitative RT-PCR. Analysis of variance with contrasts was performed to find expression patterns of the three groups (HVs, PBC, MBC).
RESULTS: We clarified the alterations of mRNA of major immune regulators PD-L1, FOXP3, CD80, CD40, and CD14 in PBMCs of cancer patients and the association of these alternations with disease progression. Furthermore, PD-L1 expression was correlated with serum interferon-γ production.
CONCLUSION: Our data suggested that mRNA expressions of PD-L1, FOXP3, CD80, CD40 and CD14 in PBMCs are affected by disease progression. Understanding the roles of these various interactions will be of importance to future studies aiming to uncover biomarkers for predicting response to immune therapy.

Huang C, Zhou L, Chang X, et al.
B7-H3, B7-H4, Foxp3 and IL-2 expression in cervical cancer: Associations with patient outcome and clinical significance.
Oncol Rep. 2016; 35(4):2183-90 [PubMed] Related Publications
The aim of this study was to determine the expression of B7-H3, B7-H4, Foxp3 and IL-2 in cervical cancer tissues, and evaluate the corresponding clinical significance. The expression of B7-H3, B7-H4, Foxp3 and IL-2 in 108 cervical cancer specimens was detected using immunohistochemistry, and their relationship with clinicopathologic parameters was determined. B7-H3, B7-H4 and Foxp3 had high levels of expression in cervical cancer cells (72.22, 80.56, and 91.56%, respectively). B7-H3 levels were only significantly associated with tumor size (P=0.013), while B7-H4, Foxp3 and IL-2 levels were significantly associated with International Federation of Gynecology and Obstetrics (FIGO) stage (P=0.023, 0.014 and 0.036, respectively) and tumor size (P=0.045, 0.010 and 0.021, respectively). Their expression levels were not correlated with age, histologic type, differentiation and lymph node metastasis (all P>0.05). Cox regression multivariate analysis confirmed that B7-H3 or B7-H4 overexpression was an independent prognostic factor. In addition, there were significant positive relationships between the expression of B7-H3 and B7-H4 with Foxp3 (P<0.001). In contrast, the expression of B7-H3 and B7-H4 was negatively correlated with IL-2 (P<0.05). B7-H3, B7-H4 and Foxp3 may be useful biomarkers in patients with cervical cancer for predicting treatment.

Tang R, Xu Y, Ma F, et al.
Extremely low frequency magnetic fields regulate differentiation of regulatory T cells: Potential role for ROS-mediated inhibition on AKT.
Bioelectromagnetics. 2016; 37(2):89-98 [PubMed] Related Publications
Our previous studies showed that extremely low frequency magnetic fields (ELF-MFs) inhibited tumor growth and change proportion of splenic regulatory T cells (Treg cells). Here, we focus on the effect of ELF-MFs on lung metastatic melanoma mouse model and the regulatory mechanism of ELF-MFs on the differentiation of Treg cells. Tumor-bearing mice were exposed to sham ELF-MFs and ELF-MFs (0.4 T, 7.5 Hz) 2 h/day for 27 days. Metastatic tumor burden of lung was significantly decreased after ELF-MF treatment. Compared to the control group, expressions of matrix metalloproteinase (MMP2, MMP9) and forkhead box P3 (Foxp3) in lung nodules significantly decreased in the ELF-MF group. Moreover, in vitro, after stimulated with anti-CD3, anti-CD28 antibodies and transforming growth factor-β (TGF-β) and treated with ELF-MFs for 2 h, expression of Foxp3 in total T cells was significantly decreased. Differentiation rate of Treg cells was inhibited from 32.0% to 22.1% by ELF-MFs. Furthermore, reactive oxygen species (ROS) was increased and phospho-serine/threonine protein kinase (p-AKT) was inhibited in both T cells and Jurkat cells. ROS scavenger N-acetyl-l-cysteine reversed inhibition of AKT pathway and expression of Foxp3 from 18.6% to 26.6% in T cells. Taken together, our data show that ELF-MF exposure promoted the inhibitory effect of ROS on AKT pathway and decreased Foxp3 expression, which provides an explanation for why ELF-MF exposure can inhibit differentiation of Treg cells and enhance antitumor effect in metastatic melanoma mouse model.

Kindlund B, Sjöling Å, Yakkala C, et al.
CD4(+) regulatory T cells in gastric cancer mucosa are proliferating and express high levels of IL-10 but little TGF-β.
Gastric Cancer. 2017; 20(1):116-125 [PubMed] Related Publications
BACKGROUND: An increase of regulatory T cells, defined as CD25(high)- and/or FOXP3(+)-expressing CD4(+) T cells, within tumors has been reported in several studies. Tregs promote tumor growth by modulating the antitumor immune response, mainly through inhibition of T-cell-mediated tumor cell killing: this has been suggested to be dependent on IL-10 and/or TGF-β. In stomach cancer, the mechanisms behind the accumulation of Tregs in tumor tissue has not been fully elucidated, and neither has Treg gene expression in situ.
MATERIALS AND METHODS: Stomach tissue from gastric cancer patients undergoing gastric resection was analyzed using flow cytometry and cell sorting, followed by RT-PCR.
RESULTS: We observed that stomach CD4(+) FOXP3(+) T cells proliferated to a higher degree than CD4(+) FOXP3(-) T cells, which may contribute to Treg accumulation in the mucosa. By analyzing DNA methylation, we demonstrated that both proliferating and nonproliferating FOXP3(+) T cells exhibited complete demethylation of the FOXP3 gene, indicating a stable FOXP3 expression in both cell populations. Furthermore, analysis of T-cell populations isolated directly from the tumor and tumor-free mucosa demonstrated that CD4(+) CD25(high) T cells have a higher IL-10/IFN-γ gene expression ratio but express lower levels of TGF-β than CD4(+) CD25(low/-) T cells.
CONCLUSION: We demonstrate strong proliferation among regulatory CD4(+) FOXP3(+) CD25(high) T cells in the gastric cancer mucosa. These local Treg express a suppressive cytokine profile characterized by high IL-10 and low TGF-β and IFN-γ production.

Yasuma K, Yasunaga J, Takemoto K, et al.
HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT).
PLoS Pathog. 2016; 12(1):e1005372 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Human T-cell leukemia virus type 1 (HTLV-1) infects CD4+ T cells and induces proliferation of infected cells in vivo, which leads to the onset of adult T-cell leukemia (ATL) in some infected individuals. The HTLV-1 bZIP factor (HBZ) gene, which is encoded in the minus strand of HTLV-1, plays critical roles in pathogenesis. In this study, RNA-seq and ChIP-seq analyses using HBZ transduced T cells revealed that HBZ upregulates the expression and promoter acetylation levels of a co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT), in addition to those of regulatory T cells related genes, Foxp3 and Ccr4. TIGIT was expressed on CD4+ T cells from HBZ-transgenic (HBZ-Tg) mice, and on ATL cells and HTLV-1 infected CD4+ T cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in vivo. Expression of Blimp1 and IL-10 was upregulated in TIGIT+CD4+ cells of HBZ-Tg mice compared with TIGIT-CD4+ T cells, suggesting the correlation between TIGIT expression and IL-10 production. When CD4+ T cells from HBZ-Tg mice were stimulated with TIGIT's ligand, CD155, their production of the inhibitory cytokine IL-10 was enhanced. Furthermore, dendritic cells from HBZ-Tg mice produced high levels of IL-10 after stimulation. These data suggest that HBZ alters immune system to suppressive state via TIGIT and IL-10. Importantly, TIGIT suppressed T-cell responses to another HTLV-1 virus protein, Tax, in vitro. Blocking of TIGIT and PD-1 slightly increased anti-Tax T-cell activity in some HAM/TSP patients. These results suggest that HBZ-induced TIGIT on HTLV-1 infected cells impairs T-cell responses to viral antigens. This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to HTLV-1.

Recouvreux MS, Grasso EN, Echeverria PC, et al.
RUNX1 and FOXP3 interplay regulates expression of breast cancer related genes.
Oncotarget. 2016; 7(6):6552-65 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Runx1 participation in epithelial mammary cells is still under review. Emerging data indicates that Runx1 could be relevant for breast tumor promotion. However, to date no studies have specifically evaluated the functional contribution of Runx1 to control gene expression in mammary epithelial tumor cells. It has been described that Runx1 activity is defined by protein context interaction. Interestingly, Foxp3 is a breast tumor suppressor gene. Here we show that endogenous Runx1 and Foxp3 physically interact in normal mammary cells and this interaction blocks Runx1 transcriptional activity. Furthermore we demonstrate that Runx1 is able to bind to R-spondin 3 (RSPO3) and Gap Junction protein Alpha 1 (GJA1) promoters. This binding upregulates Rspo3 oncogene expression and downregulates GJA1 tumor suppressor gene expression in a Foxp3-dependent manner. Moreover, reduced Runx1 transcriptional activity decreases tumor cell migration properties. Collectively, these data provide evidence of a new mechanism for breast tumor gene expression regulation, in which Runx1 and Foxp3 physically interact to control mammary epithelial cell gene expression fate. Our work suggests for the first time that Runx1 could be involved in breast tumor progression depending on Foxp3 availability.

Quesada AE, Assylbekova B, Jabcuga CE, et al.
Expression of Sirt1 and FoxP3 in classical Hodgkin lymphoma and tumor infiltrating lymphocytes: Implications for immune dysregulation, prognosis and potential therapeutic targeting.
Int J Clin Exp Pathol. 2015; 8(10):13241-8 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND: Hodgkin Reed-Sternberg (HRS) cells may promote differentiation of CD4+ naïve T cells toward both FoxP3+ T regulatory (Treg) cells and TIA-1+ cytotoxic T lymphocytes (CTL). Previous studies suggest that an overabundance of cytotoxic TIA-1+ cells in relation to FoxP3+ T reg cells portends unfavorable outcomes in classical Hodgkin lymphoma (cHL), raising the possibility that its pathogenesis may be related to immune dysregulation. Sirt1 deacetylates FoxP3 and leads to decreased Treg functionality. Our objective was to compare Sirt1 and FoxP3 expressions in Hodgkin lymphoma infiltrating lymphocytes (HLIL) and confirm Sirt1 expression in HRS cells.
DESIGN: Immunohistochemical staining of paraffin-embedded tissue with antibodies to Sirt1, FoxP3, TIA-1, and CD8 was performed. Expression of Sirt1 was assessed in both the HRS cells and in the HLILs in twenty-four cases. Adequate tissue was available in 13 cHL cases to permit the enumeration of FoxP3, TIA-1 and CD8 by giving their percent staining of HLILs.
RESULTS: In HLILs, nuclear expression of Sirt1 was 32-88% (mean 67%); FoxP3 expression was 9-40% (mean 23.9%); TIA-1 expression was 15-87% (mean 32%); and CD8 expression was 10-45% (mean = 31%). Sirt1 to FoxP3 ratio was 0.96-5.5 (mean 3.2). TIA-1 to FoxP3 ratio was 0.6-5.1 (mean 1.6). CD8 to FoxP3 ratio was 0.43-3.7 (mean 1.5). There was a difference of Sirt1 to FoxP3 ratios between remission and recurrence groups, being significantly higher in the recurrence group (P = 0.005). Sirt1 demonstrated high nuclear expression in the HRS cells of 21 out of 24 (88%) cases analyzed.
CONCLUSION: The relative overexpression of Sirt1 to FoxP3 in HLILs may be considered possible targets for immune modulation. Histone deacetylase inhibitors may increase the efficacy of existing treatment regimens by downregulating SIRT1 gene mRNA/Sirt1 protein function and together with rapamycin could expand the T regulatory/FoxP3 population and functionality and improve prognosis for remission in cHL. Targeting Sirt1 in the HRS cells may facilitate their ability to promote naïve T cell differentiation toward Treg cells over CTL.

Buchynska LG, Iurchenko NP, Verko NP, et al.
FOXP3 gene promoter methylation in endometrial cancer cells.
Exp Oncol. 2015; 37(4):246-9 [PubMed] Related Publications
AIM: To determine the methylation level of promoter region of the FOXP3 gene promoter depending on the heterogeneity of intracellular localization of its protein product in endometrial cancer (EC) cells and assess its relation to the clinical and morphological features of tumor.
MATERIALS AND METHODS: Samples of surgical material of 40 EC patients who have not received any specific treatment before the surgery, were studied. Real time methylation-specific PCR (MSP) as well as morphological and immunohistochemical methods were used in the study.
RESULTS: Methylation of promoter region of the FOXP3 gene was determined in all EC cases, but variability of the methylation level in EC cells from 45.0% to 85.0% was observed. With tumor progression and in tumors with deep (≥ 1/2) invasion in myometrium, an increase of the methylation level of the FOXP3 and of cell number with cytoplasmic FOXP3 localization was observed. In EC patients the correlation between of methylation level of the FOXP3 gene and the number of FOXP3(+) tumor cells with cytoplasmic expression (r = 0.41) was determined.
CONCLUSION: The methylation level of FOXP3 gene promoter region and intracellular localization of its protein product are associated with tumor differentiation grade and the depth of myometrial invasion.

Shimazu Y, Shimazu Y, Hishizawa M, et al.
Hypomethylation of the Treg-Specific Demethylated Region in FOXP3 Is a Hallmark of the Regulatory T-cell Subtype in Adult T-cell Leukemia.
Cancer Immunol Res. 2016; 4(2):136-45 [PubMed] Related Publications
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1. Because of its immunosuppressive property and resistance to treatment, patients with ATL have poor prognoses. ATL cells possess the regulatory T cell (Treg) phenotype, such as CD4 and CD25, and usually express forkhead box P3 (FOXP3). However, the mechanisms of FOXP3 expression and its association with Treg-like characteristics in ATL remain unclear. Selective demethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 gene leads to stable FOXP3 expression and defines natural Tregs. Here, we focus on the functional and clinical relationship between the epigenetic pattern of the TSDR and ATL. Analysis of DNA methylation in specimens from 26 patients with ATL showed that 15 patients (58%) hypomethylated the TSDR. The FOXP3(+) cells were mainly observed in the TSDR-hypomethylated cases. The TSDR-hypomethylated ATL cells exerted more suppressive function than the TSDR-methylated ATL cells. Thus, the epigenetic analysis of the FOXP3 gene identified a distinct subtype with Treg properties in heterogeneous ATL. Furthermore, we observed that the hypomethylation of TSDR was associated with poor outcomes in ATL. These results suggest that the DNA methylation status of the TSDR is an important hallmark to define this heterogeneous disease and to predict ATL patient prognosis.

Li Y, Li D, Yang W, et al.
Overexpression of the transcription factor FOXP3 in lung adenocarcinoma sustains malignant character by promoting G1/S transition gene CCND1.
Tumour Biol. 2016; 37(6):7395-404 [PubMed] Related Publications
The Forkhead box P3 (FOXP3) transcription factor is the key driver of the differentiation and immunosuppressive function of regulatory T cells (Tregs). Additionally, FOXP3 has been reported to be expressed in many solid tumor cell lines and tissues. However, its role in tumorigenesis and tumor progression is conflicting, both tumor suppressive and promoting functions have been described. In this study, we demonstrated that FOXP3 was expressed in both lung adenocarcinoma tissues and the lung adenocarcinoma cell line A549. FOXP3 inhibition decreased cell proliferation, migration, and invasion as well as the secretion of inhibitory cytokines (e.g., transforming growth factor beta 1 (TGF-β1), interleukin 35 (IL-35), and heme oxygenase-1 (HMOX1)), suggesting a positive role for FOXP3 in tumor development. Importantly, we found that FOXP3 could enhance lung adenocarcinoma cell proliferation via upregulating the levels of the cell cycle G1/S checkpoint gene CCND1. These data demonstrated that FOXP3 could be regarded as a novel therapeutic target for inhibiting lung adenocarcinoma progression.

Molinier-Frenkel V, Mestivier D, Castellano F
Alterations of the immunosuppressive IL4I1 enzyme activity induced by naturally occurring SNP/mutations.
Genes Immun. 2016; 17(2):148-52 [PubMed] Related Publications
The immunosuppressive phenylalanine oxidase interleukin 4-induced gene 1 (IL4I1), primarily produced by antigen-presenting cells, inhibits T-cell proliferation and promotes the generation of Foxp3(+) regulatory T cells in vitro. Highly expressed by tumour-associated macrophages from human cancers, IL4I1 has a potential role in immune evasion from the anti-tumour immune response. We have reviewed single-nucleotide polymorphisms (SNPs) and mutations described for the exon 4 of the IL4I1 isoform 1, which is expressed in lymphoid tissue. Two of them were expressed in an exogenous system to analyse their effect on the enzymatic activity. The N92D SNP leads to a hyperactive enzyme, while the R102G mutation is hypomorphic. Moreover, we show that IL4I1 activity is not only directed against phenylalanine, as initially described, but also at a lower level against arginine. These data pave the way to more extensive analyses of the mutational state of IL4I1 in pathological conditions such as cancer, where its participation in immune system dysfunctions may have therapeutic implications.

Yoon SO, Kim EK, Lee M, et al.
NOVA1 inhibition by miR-146b-5p in the remnant tissue microenvironment defines occult residual disease after gastric cancer removal.
Oncotarget. 2016; 7(3):2475-95 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Occult residual disease in remnant tissues could be the cause of tumor relapse. To identify signal molecules and target cells that may be indicative of occult residual disease within a remnant microenvironment, proximal resection margin tissues of gastric cancers were used, as these correspond to the nearest remnant tissues after gastrectomy. Increased miR-146b-5p in the remnant microenvironment was determined to be a strong risk factor for tumor relapse and poor survival rate. NOVA1, a target gene of miR-146b-5p, was decreased in remnant tissues of patients with a poor prognosis. NOVA1 was enriched in stromal spindle cells such as fibroblasts within normal tissues. In non-neoplastic inflammation, such as gastritis, NOVA1 was highly enriched in T lymphocytes and stromal spindle cells, while expression of this protein was frequently decreased in those types of cells within gastric cancer tissues. Particularly, decreased NOVA1 in T cells within the gastric cancer tissues was correlated with decreased FOXP3-positive regulatory T cells and was associated with poor patient prognosis. In vitro analysis showed that the NOVA1 gene was inhibited by miR-146b-5p. In immune cells as well as stromal spindle cells, decreased NOVA1, possibly inhibited by miR-146b-5p, is a candidate biomarker predicting poor prognosis of gastric cancer patients and is also a biomarker of occult residual disease in remnant tissues after gastric cancer removal.

Hayakawa S, Okada S, Tsumura M, et al.
A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer.
J Clin Immunol. 2016; 36(1):28-32 [PubMed] Related Publications
Cytotoxic T-lymphocyte-antigen 4 (CTLA-4) is an essential negative regulator expressed on regulatory T cells (Tregs) and activated T cells. Germline heterozygous mutations in CTLA4 lead to haploinsufficiency of CTLA-4, resulting in the development of an autosomal dominant immune dysregulation syndrome with incomplete penetrance. We report here a Japanese patient with this disorder who has a novel heterozygous single nucleotide insertion, 76_77insT (p. L28SfsX40), in the CTLA4 gene. Peripheral blood mononuclear cells from the patient showed decreased frequency of CTLA-4(high) cells in CD4(+)FOXP3(+) cells following CD3/CD28 stimulation. The patient experienced hypogammaglobulinemia, recurrent pneumonia, esophageal candidiasis, cytomegalovirus-positive chronic gastritis, chronic and severe diarrhea, and type 1 diabetes mellitus. Moreover, the patient developed multifocal gastric cancer, histologically poorly and well-differentiated adenocarcinomas, associated with chronic atrophic gastritis and intestinal metaplasia. Previously, 23 symptomatic cases with heterozygous CTLA4 mutations have been reported. Including the case presented here, 3 of the 24 cases (12.5%) developed gastric cancer. Notably, 2 of 3 patients presented similarly multifocal adenocarcinomas associated with atrophic gastritis and intestinal metaplasia. Predisposition to gastric cancer has been also reported in CVID patients. These clinical observations suggest that gastric cancer is a disease commonly associated with autosomal dominant immune dysregulation syndrome due to CTLA4 mutation.

Wang Q, Luan W, Warren L, et al.
Prognostic Role of Immune Cells in Hepatitis B-associated Hepatocellular Carcinoma Following Surgical Resection Depends on Their Localization and Tumor Size.
J Immunother. 2016; 39(1):36-44 [PubMed] Related Publications
This study aims to evaluate localized expression of CD4, interleukin (IL)-17, Foxp3, and CD8 in hepatitis B-associated hepatocellular carcinoma (HBV-HCC) and to explore their potential effects on outcome following surgical resection. This prospective study includes 66 HBV-HCC surgical resection patients enrolled from 2008 to 2013. CD4, IL-17, Foxp3, and CD8 mRNA in 4 regions of the resection specimens (center of the tumor, periphery of the tumor, non-neoplastic liver bordering tumor, non-neoplastic liver distant from tumor) was quantitated using real-time polymerase chain reaction. The tumoral regions had lower CD4 and CD8 expression as compared with paired non-neoplastic regions, whereas the expression of IL-17 and Foxp3 did not differ. High Foxp3 in all regions except non-neoplastic liver distant from tumor was associated with poor overall survival, whereas low CD8 expression in distant non-neoplastic liver may be associated with high HCC recurrence rate. Although the expression of almost all molecules did not differ between small (≤3 cm) and large HCC (>3 cm), high IL-17 in periphery of tumor, high CD8 in center of tumor, or low CD8 in distant non-neoplastic liver was associated with high HCC recurrence rate in patients with small HCC, but not in those with large HCC. The effect of immune cells on HCC progression therefore depends on the expression level, localization, and tumor size, and an imbalance toward regulatory T cells is associated with poor outcome.

Kumra H, Reinhardt DP
Fibronectin-targeted drug delivery in cancer.
Adv Drug Deliv Rev. 2016; 97:101-10 [PubMed] Related Publications
Fibronectin is an extracellular matrix protein with pivotal physiological and pathological functions in development and adulthood. Alternative splicing of the precursor mRNA, produced from the single copy fibronectin gene, occurs at three sites coding for the EDA, EDB and IIICS domains. Fibronectin isoforms comprising the EDA or EDB domains are known as oncofetal forms due to their developmental importance and their re-expression in tumors, contrasting with restricted presence in normal adult tissues. These isoforms are also recognized as important markers of angiogenesis, a crucial physiological process in development and required by tumor cells in cancer progression. Attributed to this feature, EDA and EDB domains have been extensively used for the targeted delivery of cytokines, cytotoxic agents, chemotherapy drugs and radioisotopes to fibronectin-expressing tumors to exert therapeutic effects on primary cancers and metastatic lesions. In addition to drug delivery, the EDA and EDB domains of fibronectin have also been utilized to develop imaging strategies for tumor tissues. Furthermore, EDA and EDB based vaccines seem to be promising for the treatment and prevention of certain cancer types. In this review, we will summarize recent advances in fibronectin EDA and EDB-based therapeutic strategies developed to treat cancer.

Ohshima K
Molecular Pathology of Adult T-Cell Leukemia/Lymphoma.
Oncology. 2015; 89 Suppl 1:7-15 [PubMed] Related Publications
Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm of highly pleomorphic lymphoid cells. ATLL is usually widely disseminated, and it is caused by human T-cell leukemia virus type 1 (HTLV-1). It is a disease with a long latency, and affected individuals are usually exposed to the virus very early in life. The cumulative incidence of ATLL is estimated to be 2.5% among HTLV-1 carriers. ATLL cells express CD2, CD3, CD5, CD4, and CD25, as well as CCR4 and FoxP3 of the regulatory T-cell marker. HTLV-1 is causally linked to ATLL, but infection alone is not sufficient to result in neoplastic transformation. A significant finding in this connection is that the Tax viral protein leads to transcriptional activation of many genes, while the HTLV-1 basic leucine zipper factor is thought to be important for T-cell proliferation and oncogenesis. Half of ATLL cases retain the ability to express HTLV-1 Tax, which is a target of HTLV-1-specific cytotoxic T lymphocytes (CTL). An increase in HTLV-1-specific CTL responses is observed in some asymptomatic HTLV-1 carriers. Although HTLV-1-specific CTL are also present in the peripheral blood of ATLL patients, they do not expand sufficiently. We investigated the clinicopathological features and analyzed the staining of Tax-specific CTL and FoxP3. Tax-specific CTL correlated inversely with FoxP3, an increase in the ratio of CD163+ tumor-associated macrophages was associated with worse clinical prognosis, and ATLL cell lines proliferated significantly following direct co-culture with M2 macrophages. Several clinical variants of ATLL have been identified: acute, lymphomatous, chronic, and smoldering. Oligo-array comparative genomic hybridization revealed that genomic loss of 9p21.3 was a significant characteristic of acute-type, but not of chronic-type ATLL. Furthermore, we found that genomic alteration of CD58, which is implicated in immune escape, is more frequently observed in acute than in chronic ATLL. Interestingly, the chronic cases with cell cycle deregulation and disruption of immunosurveillance mechanism were associated with faster progression to acute ATLL. Immune evasion, microenvironment, and genetic alteration are therefore important in the multi-step progression of ATLL lymphomagenesis.

Zhang H, Li ZL, Ye SB, et al.
Myeloid-derived suppressor cells inhibit T cell proliferation in human extranodal NK/T cell lymphoma: a novel prognostic indicator.
Cancer Immunol Immunother. 2015; 64(12):1587-99 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
The expansion of myeloid-derived suppressor cells (MDSCs) and its correlation with advanced disease stage have been shown in solid cancers. Here, we investigated the functional features and clinical significance of MDSCs in extranodal NK/T cell lymphoma (ENKL). A higher percentage of circulating HLA-DR(-)CD33(+)CD11b(+) MDSCs was observed in ENKL patients than in healthy controls (P < 0.05, n = 32) by flow cytometry analysis. These MDSCs from ENKL patients (ENKL-MDSCs) consisted of CD14(+) monocytic (Mo-MDSCs, >60 %) and CD15(+) granulocytic (PMN-MDSCs, <20 %) MDSCs. Furthermore, these ENKL-MDSCs expressed higher levels of Arg-1, iNOS and IL-17 compared to the levels of MDSCs from healthy donors, and they expressed moderate levels of TGFβ and IL-10 but lower levels of CD66b. The ENKL-MDSCs strongly suppressed the anti-CD3-induced allogeneic and autologous CD4 T cell proliferation (P < 0.05), but they only slightly suppressed CD8 T cell proliferation (P > 0.05). Interestingly, ENKL-MDSCs inhibited the secretion of IFNγ but promoted IL-10, IL-17 and TGFβ secretion as well as Foxp3 expression in T cells. The administration of inhibitors of iNOS, Arg-1 and ROS significantly reversed the suppression of anti-CD3-induced T cell proliferation by MDSCs (P < 0.05). Importantly, based on multivariate Cox regression analysis, the HLA-DR(-)CD33(+)CD11b(+) cells and CD14(+) Mo-MDSCs were independent predictors for disease-free survival (DFS, P = 0.013 and 0.016) and overall survival (OS, P = 0.017 and 0.027). Overall, our results identified for the first time that ENKL-MDSCs (mainly Mo-MDSCs) have a prognostic value for patients and a suppressive function on T cell proliferation.

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