Gene Summary

Gene:FOXP3; forkhead box P3
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:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:forkhead box protein P3
Source:NCBIAccessed: 29 August, 2019


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

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 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.

  • Single Nucleotide Polymorphism
  • Interleukin-17
  • CD4-Positive T-Lymphocytes
  • Republic of Korea
  • Single-Stranded Conformational Polymorphism
  • Immunohistochemistry
  • Cell Proliferation
  • Promoter Regions
  • Survival Rate
  • CD Antigens
  • X Chromosome
  • FOXP3
  • Colorectal Cancer
  • Phenotype
  • Mutation
  • CD8-Positive T-Lymphocytes
  • B7-H1 Antigen
  • Serum Albumin
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Polymorphism
  • Gene Expression Profiling
  • Biomarkers, Tumor
  • Forkhead Transcription Factors
  • Lymphocytes, Tumor-Infiltrating
  • Gene Expression
  • Vocal Cords
  • Proportional Hazards Models
  • T-Lymphocytes
  • Skin Cancer
  • Estrogen Receptors
  • Adenocarcinoma
  • Transcriptional Regulator ERG
  • Breast Cancer
  • Messenger RNA
  • Staging
  • Precision Medicine
  • beta 2-Microglobulin
  • Cancer Gene Expression Regulation
  • Prostate Cancer
  • Melanoma
Tag cloud generated 29 August, 2019 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)

Zhou J, Jiang Y, Zhang H, et al.
Clinicopathological implications of TIM3
Cancer Immunol Immunother. 2019; 68(7):1157-1169 [PubMed] Related Publications
Chordoma is difficult to eradicate due to high local recurrence rates. The immune microenvironment is closely associated with tumor prognosis; however, its role in skull base chordoma is unknown. The expression of Galectin-9 (Gal9) and tumor-infiltrating lymphocyte (TIL) markers was assessed by immunohistochemistry. Kaplan-Meier and multivariate Cox analyses were used to assessing local recurrence-free survival (LRFS) and overall survival (OS) of patients. MiR-455-5p was identified as a regulator of Gal9 expression. Immunopositivity for Gal9 was associated with tumor invasion (p = 0.019), Karnofsky performance status (KPS) score (p = 0.017), and total TIL count (p < 0.001); downregulation of miR-455-5p was correlated with tumor invasion (p = 0.017) and poor prognosis; and the T-cell immunoglobulin and mucin-domain 3 (TIM3)

Henrik Heiland D, Ravi VM, Behringer SP, et al.
Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma.
Nat Commun. 2019; 10(1):2541 [PubMed] Free Access to Full Article Related Publications
Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFβ, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.

Cezar-Dos-Santos F, Ferreira RS, Okuyama NCM, et al.
FOXP3 immunoregulatory gene variants are independent predictors of human papillomavirus infection and cervical cancer precursor lesions.
J Cancer Res Clin Oncol. 2019; 145(8):2013-2025 [PubMed] Related Publications
PURPOSE: FOXP3 is a marker of the T regulatory (Treg) cell subset and drives its function and homeostasis. Its expression maintains the host immunosuppressive state that favors persistence of human papillomavirus (HPV) infection and squamous intraepithelial lesion (SIL) appearance. The present study evaluated the effects of the rs3761548 and rs2232365 intronic single-nucleotide variants (SNVs) and their haplotypes on HPV infection and SIL diagnosis in HPV-infected and -uninfected women.
METHODS: HPV DNA-based detection in cervical specimens was performed by PCR. FOXP3 variants were genotyped by PCR-restriction fragment length polymorphism and haplotype recombination sites were inferred for 208 HPV-infected and 218 HPV-uninfected women diagnosed or not with low- or high-grade intraepithelial lesions of cervix. Case-control analyses were carried out by logistic regression adjusted for several socio-demographic, sexual lifestyle, and clinical data.
RESULTS: The homozygous genotype of the rs3761548 variants (A/A) (related to decreased FOXP3 expression) may exert a protective role against HPV infection in women (OR
CONCLUSIONS: Our results reveal the significant and independent associations between FOXP3 genetic variants and susceptibility to HPV infection and SIL diagnosis and their role as biomarkers of HPV infection and cervical lesion management.

Yang MW, Fu XL, Jiang YS, et al.
Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas.
World J Gastroenterol. 2019; 25(14):1684-1696 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas (G-NECs) remains unknown.
AIM: To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant.
METHODS: We investigated the expression of PD-L1 on tumor cells and PD-1
RESULTS: Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43 G-NECs, 21 (48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival (OS). The high expression of PD-L1 was correlated with abundant PD-1
CONCLUSION: Our data demonstrated for the first time that high expression of PD-L1 in G-NECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in G-NECs.

Sadahiro S, Suzuki T, Tanaka A, et al.
Induction of CD3+ and FoxP3+ T Cells in Left-sided Colorectal Tumors After UFT/LV Chemotherapy.
Anticancer Res. 2019; 39(4):1997-2005 [PubMed] Related Publications
BACKGROUND/AIM: Immune checkpoint inhibitors are mainly used for right-sided, microsatellite instability-high colorectal tumors. In this study, the effects of oral uracil-tegafur plus leucovorin (UFT/LV) chemotherapy on the gene expressions of four immunotherapy targets and the amounts of tumor-infiltrating lymphocytes (TILs) were investigated.
PATIENTS AND METHODS: Data of 260 patients with stage II or stage III colorectal cancer were analyzed. Gene expression and amount of TILs were evaluated using real-time reverse transcription polymerase chain reaction (CRT-PCR) assay and immunohistochemical staining, respectively.
RESULTS: Expression of CTLA4 and LAG3 in tumor tissues was significantly increased after UFT/LV chemotherapy, but only in left-sided tumors. The percentage of high-TIL, high-CD3 and high-FoxP3 patients in the UFT/LV group was significantly higher than that in the control group, only in left-sided tumors.
CONCLUSION: The increase in TILs count, especially of CD3+ T cells and FoxP3+ regulatory T cells, after UFT/LV chemotherapy were specific to left-sided colorectal cancers.

Barilla RM, Diskin B, Caso RC, et al.
Specialized dendritic cells induce tumor-promoting IL-10
Nat Commun. 2019; 10(1):1424 [PubMed] Free Access to Full Article Related Publications
The drivers and the specification of CD4

Carreras J, Lopez-Guillermo A, Kikuti YY, et al.
High TNFRSF14 and low BTLA are associated with poor prognosis in Follicular Lymphoma and in Diffuse Large B-cell Lymphoma transformation.
J Clin Exp Hematop. 2019; 59(1):1-16 [PubMed] Free Access to Full Article Related Publications
The microenvironment influences the behavior of follicular lymphoma (FL) but the specific roles of the immunomodulatory BTLA and TNFRSF14 (HVEM) are unknown. Therefore, we examined their immunohistochemical expression in the intrafollicular, interfollicular and total histological compartments in 106 FL cases (57M/49F; median age 57-years), and in nine relapsed-FL with transformation to DLBCL (tFL). BTLA expression pattern was of follicular T-helper cells (TFH) in the intrafollicular and of T-cells in the interfollicular compartments. The mantle zones were BTLA+ in 35.6% of the cases with similar distribution of IgD. TNFRSF14 expression pattern was of neoplastic B lymphocytes (centroblasts) and "tingible body macrophages". At diagnosis, the averages of total BTLA and TNFRSF14-positive cells were 19.2%±12.4STD (range, 0.6%-58.2%) and 46.7 cells/HPF (1-286.5), respectively. No differences were seen between low-grade vs. high-grade FL but tFL was characterized by low BTLA and high TNFRSF14 expression. High BTLA correlated with good overall survival (OS) (total-BTLA, Hazard Risk=0.479, P=0.022) and with high PD-1 and FOXP3+Tregs. High TNFRSF14 correlated with poor OS and progression-free survival (PFS) (total-TNFRSF14, HR=3.9 and 3.2, respectively, P<0.0001), with unfavorable clinical variables and higher risk of transformation (OR=5.3). Multivariate analysis including BTLA, TNFRSF14 and FLIPI showed that TNFRSF14 and FLIPI maintained prognostic value for OS and TNFRSF14 for PFS. In the GSE16131 FL series, high TNFRSF14 gene expression correlated with worse prognosis and GSEA showed that NFkB pathway was associated with the "High-TNFRSF14/dead-phenotype".In conclusion, the BTLA-TNFRSF14 immune modulation pathway seems to play a role in the pathobiology and prognosis of FL.

Wang L, Li B, Zhang L, et al.
miR-664a-3p functions as an oncogene by targeting Hippo pathway in the development of gastric cancer.
Cell Prolif. 2019; 52(3):e12567 [PubMed] Related Publications
OBJECTIVES: It has been accounted that miR-664a-3p has different functions in several malignancies; however, the precise role and underlying mechanism in gastric cancer have not been elucidated. Our study aims to explore the function of miR-664a-3p on the progression of gastric cancer (GC).
METHODS: qRT-PCR was applied to detect the expression of miR-664a-3p in GC tissues and cells. The functions of miR-664a-3p on GC in vitro were examined by cell proliferation assay, and transwell assay. Related proteins of epithelial-mesenchymal transition (EMT) and signal pathway were evaluated by Western blot and immunofluorescence analysis. The bioinformatic, dual-luciferase assay or ChIP assay were employed to identify the interaction between miR-664a-3p and its target gene or Foxp3. The effects in vivo were investigated through a mouse tumorigenicity model.
RESULTS: miR-664a-3p was frequently upregulated in GC tissues and cells. Elevated expression of miR-664a-3p significantly promoted proliferation and invasion in vitro and in vivo. MOB1A was confirmed to be a target of miR-664a-3p and restoration of MOB1A attenuated the effects of miR-664a-3p. A series of investigations indicated that miR-664a-3p contributed to EMT process and inactivated the Hippo pathway by downregulating MOB1A.
CONCLUSION: Taken together, we revealed that miR-664a-3p functions as an oncogene by targeting Hippo pathway in the development of gastric cancer.

Wing JB, Tanaka A, Sakaguchi S
Human FOXP3
Immunity. 2019; 50(2):302-316 [PubMed] Related Publications
Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a critical role in the maintenance of immune homeostasis and prevention of autoimmunity. Recent advances in single cell analyses have revealed a range of Treg cell activation and differentiation states in different human pathologies. Here we review recent progress in the understanding of human Treg cell heterogeneity and function. We discuss these findings within the context of concepts in Treg cell development and function derived from preclinical models and insight from approaches targeting Treg cells in clinical settings. Distinguishing functional Treg cells from other T cells and understanding the context-dependent function(s) of different Treg subsets will be crucial to the development of strategies toward the selective therapeutic manipulation of Treg cells in autoimmunity and cancer.

Park YJ, Ryu H, Choi G, et al.
IL-27 confers a protumorigenic activity of regulatory T cells via CD39.
Proc Natl Acad Sci U S A. 2019; 116(8):3106-3111 [PubMed] Free Access to Full Article Related Publications
Expression of ectonucleotidase CD39 contributes to the suppressive activity of Foxp3

Rahman MR, Islam T, Gov E, et al.
Identification of Prognostic Biomarker Signatures and Candidate Drugs in Colorectal Cancer: Insights from Systems Biology Analysis.
Medicina (Kaunas). 2019; 55(1) [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, but early diagnosis ameliorates the survival of CRC. This report aimed to identify molecular biomarker signatures in CRC. We analyzed two microarray datasets (GSE35279 and GSE21815) from the Gene Expression Omnibus (GEO) to identify mutual differentially expressed genes (DEGs). We integrated DEGs with protein⁻protein interaction and transcriptional/post-transcriptional regulatory networks to identify reporter signaling and regulatory molecules; utilized functional overrepresentation and pathway enrichment analyses to elucidate their roles in biological processes and molecular pathways; performed survival analyses to evaluate their prognostic performance; and applied drug repositioning analyses through Connectivity Map (CMap) and geneXpharma tools to hypothesize possible drug candidates targeting reporter molecules. A total of 727 upregulated and 99 downregulated DEGs were detected. The PI3K/Akt signaling, Wnt signaling, extracellular matrix (ECM) interaction, and cell cycle were identified as significantly enriched pathways. Ten hub proteins (ADNP, CCND1, CD44, CDK4, CEBPB, CENPA, CENPH, CENPN, MYC, and RFC2), 10 transcription factors (ETS1, ESR1, GATA1, GATA2, GATA3, AR, YBX1, FOXP3, E2F4, and PRDM14) and two microRNAs (miRNAs) (miR-193b-3p and miR-615-3p) were detected as reporter molecules. The survival analyses through Kaplan⁻Meier curves indicated remarkable performance of reporter molecules in the estimation of survival probability in CRC patients. In addition, several drug candidates including anti-neoplastic and immunomodulating agents were repositioned. This study presents biomarker signatures at protein and RNA levels with prognostic capability in CRC. We think that the molecular signatures and candidate drugs presented in this study might be useful in future studies indenting the development of accurate diagnostic and/or prognostic biomarker screens and efficient therapeutic strategies in CRC.

Laissue P
The forkhead-box family of transcription factors: key molecular players in colorectal cancer pathogenesis.
Mol Cancer. 2019; 18(1):5 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is the third most commonly occurring cancer worldwide and the fourth most frequent cause of death having an oncological origin. It has been found that transcription factors (TF) dysregulation, leading to the significant expression modifications of genes, is a widely distributed phenomenon regarding human malignant neoplasias. These changes are key determinants regarding tumour's behaviour as they contribute to cell differentiation/proliferation, migration and metastasis, as well as resistance to chemotherapeutic agents. The forkhead box (FOX) transcription factor family consists of an evolutionarily conserved group of transcriptional regulators engaged in numerous functions during development and adult life. Their dysfunction has been associated with human diseases. Several FOX gene subgroup transcriptional disturbances, affecting numerous complex molecular cascades, have been linked to a wide range of cancer types highlighting their potential usefulness as molecular biomarkers. At least 14 FOX subgroups have been related to CRC pathogenesis, thereby underlining their role for diagnosis, prognosis and treatment purposes.This manuscript aims to provide, for the first time, a comprehensive review of FOX genes' roles during CRC pathogenesis. The molecular and functional characteristics of most relevant FOX molecules (FOXO, FOXM1, FOXP3) have been described within the context of CRC biology, including their usefulness regarding diagnosis and prognosis. Potential CRC therapeutics (including genome-editing approaches) involving FOX regulation have also been included. Taken together, the information provided here should enable a better understanding of FOX genes' function in CRC pathogenesis for basic science researchers and clinicians.

Arabpour F, Shafizad A, Rahimzadeh M, et al.
FoxP3 gene polymorphism is associated with breast cancer in Iranian patients.
Exp Oncol. 2018; 40(4):309-314 [PubMed] Related Publications
AIM: Breast cancer (BC) is one of the leading causes of cancer death among women. Recent studies have characterized FoxP3 as a marker of regulatory T cells and an X-linked tumor suppressor gene, which is involved in the pathogenesis of BC. Therefore, we investigated the potential influence of three single-nucleotide polymorphisms (SNPs) of FoxP3 gene on the development of BC in Iranian women.
MATERIALS AND METHODS: The association between FoxP3 rs2232365, rs3761548 and rs4824747 polymorphisms and BC risk was assessed in 124 BC patients and 198 healthy controls using sequence-specific primers.
RESULTS: We identified significant difference of rs3761548 in both allele and genotype frequencies between cases and control groups. Our results showed that individuals carrying FoxP3 rs3761548 AA genotype had about 4.3-fold increased risk of BC compared with CC carriers. No significant association was found between rs3761548C>A polymorphism and clinical outcome parameters (age of onset, tumor size, lymph nodes metastasis, tumor stage, progesterone receptor status, estrogen receptor status, Ki-67 status, HER-2 status and duration of disease).
CONCLUSION: This study has provided the first genetic data on the FoxP3 gene polymorphism in south of Iran and proposes the rs3761548 polymorphism of FoxP3 gene as a risk factor, but not a prognostic marker in the development of BC in Iranian population.

Tarokhian H, Rahimi H, Mosavat A, et al.
HTLV-1-host interactions on the development of adult T cell leukemia/lymphoma: virus and host gene expressions.
BMC Cancer. 2018; 18(1):1287 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder of HTLV-1-host interactions in infected TCD4+ cells. In this study, the HTLV-1 proviral load (PVL) and HBZ as viral elements and AKT1, BAD, FOXP3, RORγt and IFNλ3 as the host factors were investigated.
METHODS: The study was conducted in ATLLs, HTLV-1-associated myelopathy/tropical spastic paraparesis patients (HAM/TSPs) and HTLV-1-asympthomatic carriers (ACs). The DNA and mRNA from peripheral blood mononuclear cells were extracted for gene expression assessments via qRT-PCR, TaqMan assay, and then confirmed by western blotting.
RESULTS: As it was expected, the HTLV-1-PVL were higher in ATLLs than ACs (P = 0.002) and HAM/TSP (P = 0.041). The HBZ expression in ATLL (101.76 ± 61.3) was radically higher than in ACs (0.12 ± 0.05) and HAM/TSP (0.01 ± 0.1) (P = 0.001). Furthermore, the AKT1 expression in ATLLs (13.52 ± 4.78) was higher than ACs (1.17 ± 0.27) (P = 0.05) and HAM/TSPs (0.72 ± 0.49) (P = 0.008). However, BAD expression in ATLL was slightly higher than ACs and HAM/TSPs and not significant. The FOXP3 in ATLLs (41.02 ± 24.2) was more than ACs (1.44 ± 1) (P = 0.007) and HAM/TSP (0.45 ± 0.15) (P = 0.01). However, RORγt in ATLLs (27.43 ± 14.8) was higher than ACs (1.05 ± 0.32) (P = 0.02) but not HAM/TSPs. Finally, the IFNλ3 expression between ATLLs (31.92 ± 26.02) and ACs (1.46 ± 0.63) (P = 0.01) and ACs and HAM/TSPs (680.62 ± 674.6) (P = 0.02) were statistically different, but not between ATLLs and HAM/TSPs.
CONCLUSIONS: The present and our previous study demonstrated that HTLV-1-PVL and HBZ and host AKT1 and Rad 51 are novel candidates for molecular targeting therapy of ATLL. However, high level of RORγt may inhibit Th1 response and complicated in ATLL progressions.

Kuehnemuth B, Piseddu I, Wiedemann GM, et al.
CCL1 is a major regulatory T cell attracting factor in human breast cancer.
BMC Cancer. 2018; 18(1):1278 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Regulatory T cells (Treg) suppress cytotoxic T cell anti-tumoral immune responses and thereby promote tumor progression. Prevention of intratumoral Treg accumulation by inhibition of their migration to the tumor microenvironment is a promising therapeutic strategy. The aim of this study was to identify the role of the two major Treg-attracting chemokines CCL1 and CCL22 in human breast cancer.
METHODS: One hundred ninety-nine tissue samples of patients with invasive breast cancer were stained for CCL1 and CCL22 by immunohistochemistry. Chemokine expression and tumor infiltration by regulatory T cells, determined by expression of the transcription factor FoxP3, were quantified and their correlation to clinical features was statistically analyzed.
RESULTS: Both CCL1 and CCL22 were expressed in most breast cancer tissues. CCL1 was significantly over-expressed in invasive breast cancer as compared to normal breast tissue. CCL1, but surprisingly not CCL22, showed a significant correlation with the number of tumor-infiltrating FoxP3+ Treg (p< 0.001). High numbers of intratumoral CCL1 expressing cells were related to high grade tumors (G4) and a positive estrogen receptor (ER) status whereas high CCL22 expression was generally seen in lower grade tumors. The median survival of 88 patients with high intratumoral CCL1 expression was 37 months compared to 50 months for the 87 patients with low CCL1 levels, this trend was however not statistically significant.
CONCLUSIONS: We found a high expression of CCL1 in human breast cancer. CCL1 significantly correlated with the infiltration of immunosuppressive FoxP3+ Treg, that are known to negatively affect survival. Thus, CCL1 may serve as prognostic marker and novel therapeutic target in breast cancer.

Zheng X, Dong L, Wang K, et al.
MiR-21 Participates in the PD-1/PD-L1 Pathway-Mediated Imbalance of Th17/Treg Cells in Patients After Gastric Cancer Resection.
Ann Surg Oncol. 2019; 26(3):884-893 [PubMed] Related Publications
BACKGROUND: The programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway has been shown to be involved in trauma-induced immunosuppression and to influence CD4
METHODS: In the present study, we analyzed the percentages of T-helper (Th)-17/regulatory T (Treg) cells and PD-1/PD-L1 expression on peripheral blood mononuclear cells (PBMCs) during the perioperative period. We also detected the secretion of interleukin (IL)-17 and transforming growth factor (TGF)-β1 using enzyme-linked immunosorbent assays (ELISAs). Furthermore, PBMCs isolated from patients were transfected with or without adenovirus-short hairpin-PD-1 (Ad-sh-PD1), pre-miR-21 or adenovirus-green fluorescent protein (Ad-GFP), and the percentages of Th17/Treg cells and related transcription factors were measured.
RESULTS: In patients who underwent gastric cancer resection, the number of Th17 cells decreased, whereas the number of Treg cells increased, accompanied by an increased expression of PD-1/PD-L1. In addition, the expression of RORγt and IL-17 decreased, whereas the expression of Foxp3 and TGF-β1 increased. In vitro, silencing PD-1 via Ad-sh-PD1 promoted the expression of miR-21 and increased the percentage of Th17 cells, but decreased the percentage of Treg cells. The overexpression of miR-21 increased the percentage of Th17 cells but decreased the percentage of Treg cells.
CONCLUSIONS: Our study demonstrated that gastric cancer resection altered the balance of Th17/Treg cells and increased PD-1/PD-L1 expression. In the in vitro experiments, the transfection of Ad-sh-PD1 ameliorated Th17/Treg cell imbalance partially by increasing the expression of miR-21.

Li W, Blessin NC, Simon R, et al.
Expression of the immune checkpoint receptor TIGIT in Hodgkin's lymphoma.
BMC Cancer. 2018; 18(1):1209 [PubMed] Free Access to Full Article Related Publications
Hodgkin's lymphoma (HL) is characterized by a high background of inflammatory cells which play an important role for the pathogenesis of the disease. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor and a putative target for novel immunotherapies. To study patterns of TIGIT expression in the T cell background surrounding malignant cells including Hodgkin cells, Reed-Sternberg cells and histiocytic cells, a microenvironment (ME) tissue microarray (TMA) was constructed from tissue punches measuring 2 mm in diameter obtained from formalin-fixed tissue samples of Hodgkin's lymphoma lymph nodes (n = 40) and normal human tonsil (n = 2). The ME-TMA was stained by brightfield and fluorescence multiplex immunohistochemistry (IHC) to evaluate expression levels of TIGIT and PD-1 as well as standard lymphocyte markers (CD3, CD8, CD4, FOXP3) in the lymphocytic background. All analyzed cases of HL contained 9-99% (median: 86%) of TIGIT

Zhu F, Yi G, Liu X, et al.
Ring finger protein 31-mediated atypical ubiquitination stabilizes forkhead box P3 and thereby stimulates regulatory T-cell function.
J Biol Chem. 2018; 293(52):20099-20111 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
The CD4

Magnuson AM, Kiner E, Ergun A, et al.
Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types.
Proc Natl Acad Sci U S A. 2018; 115(45):E10672-E10681 [PubMed] Article available free on PMC after 28/12/2019 Related Publications

Meng X, Gao Y, Yang L, et al.
Immune Microenvironment Differences Between Squamous and Non-squamous Non-small-cell Lung Cancer and Their Influence on the Prognosis.
Clin Lung Cancer. 2019; 20(1):48-58 [PubMed] Related Publications
INTRODUCTION: Checkpoint blockades have entered routine clinical use for non-small-cell lung cancer (NSCLC). However, there were some differences in efficacy and response predictors for anti-programmed cell death protein 1 (PD-1) antibodies between squamous (SQ) and nonsquamous (non-SQ) NSCLC. The study aims to elucidate the possible difference in immune microenvironment between SQ-NSCLC and non-SQ-NSCLC and their influence on the prognosis.
PATIENTS AND METHODS: A total of 197 patients with stages I to III NSCLC were included. cluster of differentiation 8 (CD8), cluster of differentiation 4 (CD4), transcription factor forkhead box P3 (FOXP3), and programmed death-ligand 1 (PD-L1) expression were examined in cancer nest and stroma on 85 SQ-NSCLC and 112 non-SQ-NSCLC samples using immunohistochemistry.
RESULTS: More CD8+ tumor infiltrating lymphocytes (TILs) were detected in the cancer nests (cCD8) from patients with SQ-NSCLC than those with non-SQ-NSCLC (56% vs. 34%; P = .002). There were no significant differences between the SQ and non-SQ groups in terms of other TIL markers or PD-L1 expression. Multivariate analysis showed that the degree of cCD8+ TIL infiltration was an independent positive predictor for overall survival (OS) in the SQ-NSCLC group (P = .003) and in the non-SQ-NSCLC group (P = .024). In the univariate analysis, CD8+ TILs in the stroma, CD4+ TILs in the cancer nest and stroma, and FOXP3+ TILs in the cancer stroma associated with different prognoses for patients with either non-SQ-NSCLC or SQ-NSCLC. Using a 10% cutoff, PD-L1 expression was a poor prognostic factor in total NSCLC (P = .011), stage I (P = .037), SQ-NSCLC (P = .097), and non-SQ-NSCLC (P = .051).
CONCLUSION: The different cCD8+ TIL profile and different prognostic value with certain TILs indicates that SQ-NSCLC and non-SQ-NSCLC are likely different cancer types with respect to their immune microenvironments.

Zhu M, Zhu Z, Yang J, et al.
Impact of perioperative blood transfusion on gene expression biomarkers in patients with gastrointestinal cancer.
Transfus Apher Sci. 2018; 57(5):656-660 [PubMed] Related Publications
OBJECTIVES: To explore the impacts of perioperative blood transfusion on specific pattern of inflammatory gene expression and nosocomial infections in gastrointestinal cancer patients.
METHODS: A total of 60 gastrointestinal cancer patients aged over 27 years were recruited, blood transfusion was administered to 30 patients. The peripheral venous blood was drawn from the 30 patients undergoing transfusions and messenger RNA (mRNA) was extracted from PAXGene tubes collected before surgery and at 48 h following the operation. T-helper cell subtype transcription factors were quantified using quantitative real-time polymerase chain reaction. These genes were selected based on their ability to represent specific immune pathways and their expression level of Th1, Th2 and Th17 and the major Treg-specific TFs T-bet, GATA-3, RORγt and FOXP3 were measured. Postoperative infections were documented using predefined criteria.
RESULTS: There were significantly lower in Th1-specific TF T-bet (P < 0.001) mRNA levels and significantly higher in Th2-specifc TF, GATA-3 (P < 0.001) mRNA levels assayed at 48 h. There was significantly lower in T-bet mRNA/GATA-3 (P < 0.001) mRNA ratio assayed at 48 h. There were significantly higher in Th17-specific TF RORγt (P < 0.001) and Treg-specific TF Foxp3 (P < 0.001) mRNA levels assayed at 48 h. Patients receiving a blood transfusion were more likely to develop postoperative infections (P = 0.02).
CONCLUSION: There is an association between an immunosuppressive pattern of gene expressions and blood transfusion. This gene expression profile includes a reduction in the activity of T helper cell type 1 (Th1) pathways in those patients receiving a blood transfusion. Furthermore, blood transfusion was associated with an increased susceptibility to nosocomial infections.

Wu JS, Li L, Wang SS, et al.
Autophagy is positively associated with the accumulation of myeloid‑derived suppressor cells in 4‑nitroquinoline‑1‑oxide‑induced oral cancer.
Oncol Rep. 2018; 40(6):3381-3391 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
It has previously been demonstrated that autophagy and inflammation act synergistically to promote carcinogenesis. However, the precise roles of autophagy in multistep oral carcinogenesis are still unclear, particularly regarding its association with tumor inflammation. The present study established a 4NQO‑induced oral cancer mouse model and investigated autophagy status in the multistep process of oral carcinogenesis using immunohistochemistry, western blotting and immunofluorescence staining. Furthermore, the number of Gr‑1+CD11b+ myeloid derived suppressor cells (MDSCs) and CD4+ Foxp3+ regulatory T cells (Tregs) during oral carcinogenesis and the association with autophagy status was also examined. The results revealed that the expression of autophagy biomarkers, including dihydrosphingosine 1-phosphate phosphatase LCB3 (LC3B), p62/SQSTM1 (p62) and Beclin 1 increased during 4NQO‑induced carcinogenesis and in human oral cancer. The number of MDSCs and Tregs also increased during oral carcinogenesis. Furthermore, the expression of LC3B and p62 significantly correlated with the accumulation of MDSCs and the expression of Beclin 1 correlated with the increase of Tregs. These data indicated that autophagy may be activated by the tumor inflammation microenvironment during oral carcinogenesis.

Chen YJ, Huang CH, Shi YJ, et al.
The suppressive effect of arsenic trioxide on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 expression induces apoptosis in human leukemia cells.
Toxicol Appl Pharmacol. 2018; 358:43-55 [PubMed] Related Publications
Arsenic trioxide (ATO) has been reported to inhibit the activity of Ten-eleven translocation methylcytosine dioxygenase (TET). TET modulates FOXP3 expression, while dysregulation of FOXP3 expression promotes the malignant progression of leukemia cells. We examined the role of TET-FOXP3 axis in the cytotoxic effects of ATO on the human acute myeloid leukemia cell line, U937. ATO-induced apoptosis in U937 cells was characterized by activation of caspase-3/-9, mitochondrial depolarization, and MCL1 downregulation. In addition, ATO-treated U937 cells showed ROS-mediated inhibition of TET2 transcription, leading to downregulation of FOXP3 expression and in turn, suppression of FOXP3-mediated activation of Lyn and Akt. Overexpression of FOXP3 or Lyn minimized the suppressive effect of ATO on Akt activation and MCL1 expression. Promoter luciferase activity and chromatin immunoprecipitation assays revealed the crucial role of Akt-mediated CREB phosphorylation in MCL1 transcription. Further, ATO-induced Akt inactivation promoted GSK3β-mediated degradation of MCL1. Transfection of constitutively active Akt expression abrogated ATO-induced MCL1 downregulation. MCL1 overexpression lessened the ATO-induced depolarization of mitochondrial membrane and increased the viability of ATO-treated cells. Thus, our data suggest that ATO induces mitochondria-mediated apoptosis in U937 cells through its suppressive effect on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 transcription and protein stabilization. Our findings also indicate that the same pathway underlies ATO-induced death in human leukemia HL-60 cells.

Tai YT, Lin L, Xing L, et al.
APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications.
Leukemia. 2019; 33(2):426-438 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
We investigate here how APRIL impacts immune regulatory T cells and directly contributes to the immunosuppressive multiple myeloma (MM) bone marrow (BM) microenvironment. First, APRIL receptor TACI expression is significantly higher in regulatory T cells (Tregs) than conventional T cells (Tcons) from the same patient, confirmed by upregulated Treg markers, i.e., Foxp3, CTLA-4. APRIL significantly stimulates proliferation and survival of Tregs, whereas neutralizing anti-APRIL monoclonal antibodies (mAbs) inhibit these effects. Besides TACI-dependent induction of cell cycle progression and anti-apoptosis genes, APRIL specifically augments Foxp3, IL-10, TGFβ1, and PD-L1 in Tregs to further enhance Treg-inhibited Tcon proliferation. APRIL further increases MM cell-driven Treg (iTreg) via TACI-dependent proliferation associated with upregulated IL-10, TGFβ1, and CD15s in iTreg, which further inhibits Tcons. Osteoclasts producing APRIL and PD-L1 significantly block Tcon expansion by iTreg generation, which is overcome by combined treatment with anti-APRIL and anti-PD1/PD-L1 mAbs. Finally, APRIL increases IL-10-producing B regulatory cells (Bregs) via TACI on BM Bregs of MM patients. Taken together, these results define novel APRIL actions via TACI on Tregs and Bregs to promote MM cell survival, providing the rationale for targeting APRIL/TACI system to alleviate the immunosuppressive BM milieu and improve patient outcome in MM.

Wang Y, Zhao E, Zhang Z, et al.
Association between Tim‑3 and Gal‑9 expression and gastric cancer prognosis.
Oncol Rep. 2018; 40(4):2115-2126 [PubMed] Related Publications
The T‑cell immunoglobulin and mucin domain‑containing protein 3 (Tim‑3)/galectin 9 (Gal‑9) pathway, which serves a pivotal role in immune regulation, is similar to the programmed death (PD)‑1/PD‑ligand 1 pathway. Recent evidence has suggested that Tim‑3 is differentially regulated in a variety of tumors and is a potential therapeutic target. The aim of the present study was to evaluate Tim‑3 and Gal‑9 expression and cluster of differentiation (CD)3+, CD8+ and forkhead box (FOX)p3+ T cell tumor‑infiltration in gastric cancer, as well as their impact on prognosis. Tissue samples from 587 patients with gastric cancer were used to create a tissue microarray (TMA). The immune markers Tim‑3, Gal‑9, CD3, CD8 and FOXp3 were immunostained in the TMA, and correlations with clinicopathological findings and prognosis were analyzed. Several Gene Expression Omnibus gastric cancer databases and the K‑M plotter website were used to analyze the association between the expression of Tim‑3, Gal‑9 and CD8A RNA and patient survival. The results demonstrated that Tim‑3 was mainly expressed in immune cells, with minimal expression in gastric cancer cells. Its ligand, Gal‑9, was significantly overexpressed in tumor cells. Tim‑3 and Gal‑9 expression and Foxp3+ T cell density were negatively associated with the patient overall survival (OS) rate. The density of CD8+ T cells was positively associated with the patient OS rate. Tim‑3 expression and CD8+ T cell density were revealed to be independent prognostic factors for patients with gastric cancer.

Yonekura S, Itoh M, Shiratori E, et al.
FOXP3 knockdown inhibits the proliferation and reduces NOTCH1 expression of T cell acute lymphoblastic leukemia cells.
BMC Res Notes. 2018; 11(1):582 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
OBJECTIVE: Forkhead box P3 (FOXP3) is a master transcriptional factor of regulatory T-cells (Tregs). Recent studies have shown that FOXP3 is associated with growth inhibition of cancer cells. However, the role of FOXP3 in acute T-lymphoblastic leukemia (T-ALL) cells is not known. It was also reported that NOTCH signaling promoted the expression of FOXP3 in Tregs. However, the effect of FOXP3 on NOTCH expression in T-ALL cells is little known. Therefore, we examined the effect of FOXP3 knockdown on the proliferation of T-ALL cells and NOTCH1 signaling.
RESULTS: Two T-ALL cell lines Jurkat and KOPT-K1, harboring activating NOTCH1 mutations, were transfected with small interfering RNA against FOXP3. Cell growth was assessed with a colorimetric assay and morphology was observed under a microscope. FOXP3 knockdown significantly reduced cell growth and induced morphological changes suggesting apoptosis. Quantitative polymerase chain reaction revealed that FOXP3 knockdown caused the downregulation of mRNA expression of NOTCH1 and HES1. These findings suggest that FOXP3 supports the growth of T-ALL cells although this can not be generalized because we examined only two cell lines. The observed growth suppression can be partly due to the downregulation of NOTCH1 signaling. FOXP3 may be a potential therapeutic target in T-ALL.

Lee J, Kim DM, Lee A
Prognostic Role and Clinical Association of Tumor-Infiltrating Lymphocyte, Programmed Death Ligand-1 Expression with Neutrophil-Lymphocyte Ratio in Locally Advanced Triple-Negative Breast Cancer.
Cancer Res Treat. 2019; 51(2):649-663 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
PURPOSE: Tumor-infiltrating lymphocyte (TIL), programmed death-ligand 1 (PD-L1) expression and neutrophil-to-lymphocyte ratio (NLR) is associated to immunogenicity and prognosis of breast cancer. We analyzed baseline NLR, changes of NLR, TIL, and PD-L1 during neoadjuvant chemotherapy (NAC) and their clinical implication in triple-negative breast cancer (TNBC).
Materials and Methods: Between January 2008 to December 2015, 358 TNBC patients were analyzed. Baseline NLR, 50 paired NLR (initial diagnosis, after completion of NAC) and 34 paired tissues (initial diagnosis, surgical specimen after completion of NAC) were collected. Changes of TIL, CD4, CD8, forkhead box P3 (FOXP3), and PD-L1 expression were assessed with immunohistochemical stain.
RESULTS: Low NLR (≤ 3.16) was associated to superior survival (overall survival: 41.83 months vs. 36.5 months, p=0.002; disease-free survival [DFS]: 37.85 months vs. 32.14 months, p=0.032). Modest NLR change after NAC (-30% < NLR change < 100%) showed prolonged DFS (38.37 months vs. 22.37 months, p=0.015). During NAC, negative or negative conversion of tumor PD-L1 expression was associated to poor DFS (34.77 months vs. 16.03 months, p=0.037), and same or increased TIL showed trends for superior DFS, but without statistical significance. Positive tumor PD-L1 expression (H-score ≥ 5) in baseline or post- NAC tissue was associated to superior DFS (57.6 months vs. 12.5 months, p=0.001 and 53.3 months vs. 18.9 months, p=0.040). Positive stromal PD-L1 expression in baseline was also associated to superior DFS (50.2 months vs. 20.4 months, p=0.002).
CONCLUSION: In locally advanced TNBC, baseline NLR, changes of NLR during NAC was associated to survival. Baseline PD-L1 expression and changes of PD-L1 expression in tumor tissue during NAC also showed association to prognosis.

Shan L, Ji T, Su X, et al.
TMPRSS2-ERG Fusion Promotes Recruitment of Regulatory T cells and Tumor Growth in Prostate Cancer.
Am J Med Sci. 2018; 356(1):72-78 [PubMed] Related Publications
BACKGROUND: This study was designed to examine the effect of transmembrane protease serine 2 ETS-related gene (TMPRSS2-ERG) fusion on regulatory T cells and tumor growth in prostate cancer, which may provide a new potential therapeutic direction for PCa.
METHODS: The effect of TMPRSS2-ERG fusion on the migration of Treg cells and tumor growth in a mouse model was investigated in vitro and in vivo. TMPRSS2-ERG fusion in biopsy tissues was performed by fluorescence in situ hybridization and the expression of ERG and Forkhead box P3 was detected by gel electrophoresis, real-time quantitative reverse transcription polymerase chain reaction and Western blot. Enzyme-linked immunosorbent assay and flow cytometry were used to analyze transforming growth factor β levels and the number of regulatory T cells, respectively. Finally, the infiltration of regulatory T cells was analyzed by Forkhead box P3 immunohistochemistry.
RESULTS: Fluorescence in situ hybridization analysis showed that the TMPRSS2-ERG fusion gene was positive in prostate cancer and that the messenger RNA and protein expression of ERG were significantly up-regulated in prostate cancer biopsy tissues. Furthermore, the number of regulatory T cells and the levels of Forkhead box P3 and transforming growth factor β were significantly increased in prostate cancer. TMPRSS2-ERG fusion increased the migration and activation of regulatory T cells in vitro and promoted subcutaneous tumor size and regulatory T cells infiltration in mouse models.
CONCLUSIONS: TMPRSS2-ERG fusion can regulate the recruitment and infiltration of regulatory T cells to promote tumor growth in prostate cancer.

Nam M, Shin S, Park KU, et al.
Association of FOXP3 Single Nucleotide Polymorphisms With Clinical Outcomes After Allogenic Hematopoietic Stem Cell Transplantation.
Ann Lab Med. 2018; 38(6):591-598 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
BACKGROUND: Forkhead box P3 (FOXP3) is an important marker of regulatory T cells. FOXP3 polymorphisms are associated with autoimmune diseases, cancers, and allograft outcomes. We examined whether single nucleotide polymorphisms (SNPs) at the FOXP3 locus are associated with clinical outcomes after allogenic hematopoietic stem cell transplantation (HSCT).
METHODS: Five FOXP3 SNPs (rs5902434, rs3761549, rs3761548, rs2232365, and rs2280883) were analyzed by PCR-sequencing of 172 DNA samples from allogenic HSCT patients. We examined the relationship between each SNP and the occurrence of graft-versus-host disease (GVHD), post-HSCT infection, relapse, and patient survival.
RESULTS: Patients with acute GVHD (grades II-IV) showed higher frequencies of the rs3761549 T/T genotype, rs5902434 ATT/ATT genotype, and rs2232365 G/G genotype than did patients without acute GVHD (P=0.017, odds ratio [OR]=5.3; P=0.031, OR=2.4; and P=0.023, OR=2.6, respectively). Multivariate analysis showed that the TT genotype of rs3761549 was an independent risk factor for occurrence of acute GVHD (P=0.032, hazard ratio=5.6). In contrast, the genotype frequencies of rs3761549 T/T, rs5902434 ATT/ATT, and rs2232365 G/G were lower in patients with post-HSCT infection than in patients without infection (P=0.026, P=0.046, and P=0.031, respectively).
CONCLUSIONS: rs3761549, rs5902434, and rs2232365 are associated with an increased risk of acute GVHD and decreased risk of post-HSCT infection.

Wang CM, Yang WH, Liu R, et al.
FOXP3 Activates SUMO-Conjugating
Int J Mol Sci. 2018; 19(7) [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Forkhead Box Protein P3 (FOXP3), a transcription factor of the FOX protein family, is essentially involved in the development of regulatory T (Treg) cells, and functions as a tumor suppressor. Although FOXP3 has been widely studied in immune system and cancer development, its function in the regulation of the

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