Gene Summary

Gene:TBX21; T-box transcription factor 21
Aliases: TBET, T-PET, T-bet, TBLYM
Summary:This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human ortholog of mouse Tbx21/Tbet gene. Studies in mouse show that Tbx21 protein is a Th1 cell-specific transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (IFNG). Expression of the human ortholog also correlates with IFNG expression in Th1 and natural killer cells, suggesting a role for this gene in initiating Th1 lineage development from naive Th precursor cells. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:T-box transcription factor TBX21
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (12)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 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.

  • Base Sequence
  • Knockout Mice
  • MicroRNAs
  • Forkhead Transcription Factors
  • Tetradecanoylphorbol Acetate
  • Paranasal Sinus and Nasal Cavity Cancer
  • Trastuzumab
  • Western Blotting
  • Transcription Factors
  • Signal Transduction
  • T-Cell Lymphoma
  • Young Adult
  • Lung Cancer
  • Stomach Cancer
  • Liver Cancer
  • Oligonucleotide Array Sequence Analysis
  • Breast Cancer
  • Immunohistochemistry
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • Interferon-gamma
  • Gene Expression
  • p38 Mitogen-Activated Protein Kinases
  • Immunophenotyping
  • Gene Expression Profiling
  • Case-Control Studies
  • T-Lymphocytes
  • Th1 Cells
  • Zinc Finger E-box Binding Homeobox 2
  • Natural Killer Cells
  • GATA3
  • Hodgkin Lymphoma
  • T-Box Domain Proteins
  • T-Lymphocytes, Regulatory
  • Chromosome 17
  • Leukocytes, Mononuclear
  • Transcription
  • Transfection
  • Lymphocytes
  • DNA-Binding Proteins
  • eIF-2 Kinase
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: TBX21 (cancer-related)

Noviello M, Manfredi F, Ruggiero E, et al.
Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT.
Nat Commun. 2019; 10(1):1065 [PubMed] Free Access to Full Article Related Publications
The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (T

Cao Y, Trillo-Tinoco J, Sierra RA, et al.
ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression.
Nat Commun. 2019; 10(1):1280 [PubMed] Free Access to Full Article Related Publications
Understanding the intrinsic mediators that render CD8

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

Iqbal J, Amador C, McKeithan TW, Chan WC
Molecular and Genomic Landscape of Peripheral T-Cell Lymphoma.
Cancer Treat Res. 2019; 176:31-68 [PubMed] Related Publications
Peripheral T-cell lymphoma (PTCL) is an uncommon group of lymphoma covering a diverse spectrum of entities. Little was known regarding the molecular and genomic landscapes of these diseases until recently but the knowledge is still quite spotty with many rarer types of PTCL remain largely unexplored. In this chapter, the recent findings from gene expression profiling (GEP) studies, including profiling data on microRNA, where available, will be presented with emphasis on the implication on molecular diagnosis, prognostication, and the identification of new entities (PTCL-GATA3 and PTCL-TBX21) in the PTCL-NOS group. Recent studies using next-generation sequencing have unraveled the mutational landscape in a number of PTCL entities leading to a marked improvement in the understanding of their pathogenesis and biology. While many mutations are shared among PTCL entities, the frequency varies and certain mutations are quite unique to a specific entity. For example, TET2 is often mutated but this is particularly frequent (70-80%) in angioimmunoblastic T-cell lymphoma (AITL) and IDH2 R172 mutations appear to be unique for AITL. In general, chromatin modifiers and molecular components in the CD28/T-cell receptor signaling pathways are frequently mutated. The major findings will be summarized in this chapter correlating with GEP data and clinical features where appropriate. The mutational landscape of cutaneous T-cell lymphoma, specifically on mycosis fungoides and Sezary syndrome, will also be discussed.

Wang B, Pan W, Yang M, et al.
Programmed death ligand-1 is associated with tumor infiltrating lymphocytes and poorer survival in urothelial cell carcinoma of the bladder.
Cancer Sci. 2019; 110(2):489-498 [PubMed] Free Access to Full Article Related Publications
Drugs blocking programmed death ligand-1 (PD-L1) have shown unprecedented activity in metastatic and unresectable bladder cancer. The purpose of the present study was to investigate the expression, clinical significance and association of PD-L1 with tumor-infiltrating lymphocytes (TIL) in resectable urothelial cell carcinoma of the bladder (UCB). In this retrospective study, 248 UCB patients who received radical cystectomy or transurethral resection were examined. Immunohistochemistry was used to evaluate PD-L1 expression and stromal CD8

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.

Kim HD, Song GW, Park S, et al.
Association Between Expression Level of PD1 by Tumor-Infiltrating CD8
Gastroenterology. 2018; 155(6):1936-1950.e17 [PubMed] Related Publications
BACKGROUND & AIMS: T-cell exhaustion, or an impaired capacity to secrete cytokines and proliferate with overexpression of immune checkpoint receptors, occurs during chronic viral infections but has also been observed in tumors, including hepatocellular carcinomas (HCCs). We investigated features of exhaustion in CD8
METHODS: We obtained HCC specimens, along with adjacent nontumor tissues and blood samples, from 90 patients who underwent surgical resection at Asan Medical Center (Seoul, Korea) from April 2016 through April 2018. Intrahepatic lymphocytes and tumor-infiltrating T cells were analyzed by flow cytometry. Tumor-infiltrating CD8
RESULTS: PD1-high, PD1-intermediate, and PD1-negative CD8
CONCLUSIONS: We found HCC specimens to contain CD8

Lee M, Tayyari F, Pinnaduwage D, et al.
Tumoral BRD4 expression in lymph node-negative breast cancer: association with T-bet+ tumor-infiltrating lymphocytes and disease-free survival.
BMC Cancer. 2018; 18(1):750 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We previously observed that T-bet+ tumor-infiltrating T lymphocytes (T-bet+ TILs) in primary breast tumors were associated with adverse clinicopathological features, yet favorable clinical outcome. We identified BRD4 (Bromodomain-Containing Protein 4), a member of the  Bromodomain and Extra Terminal domain (BET) family, as a gene that distinguished T-bet+/high and T-bet-/low tumors. In clinical studies, BET inhibitors have been shown to suppress inflammation in various cancers, suggesting a potential link between BRD4 and immune infiltration in cancer. Hence, we examined the BRD4 expression and clinicopathological features of breast cancer.
METHODS: The cohort consisted of a prospectively ascertained consecutive series of women with axillary node-negative breast cancer with long follow-up. Gene expression microarray data were used to detect mRNAs differentially expressed between T-bet+/high (n = 6) and T-bet-/low (n = 41) tumors. Tissue microarrays (TMAs) constructed from tumors of 612 women were used to quantify expression of BRD4 by immunohistochemistry, which was analyzed for its association with T-bet+ TILs, Jagged1, clinicopathological features, and disease-free survival.
RESULTS: Microarray analysis indicated that BRD4 mRNA expression was up to 44-fold higher in T-bet+/high tumors compared to T-bet-/low tumors (p = 5.38E-05). Immunohistochemical expression of BRD4 in cancer cells was also shown to be associated with T-bet+ TILs (p = 0.0415) as well as with Jagged1 mRNA and protein expression (p = 0.0171, 0.0010 respectively). BRD4 expression correlated with larger tumor size (p = 0.0049), pre-menopausal status (p = 0.0018), and high Ki-67 proliferative index (p = 0.0009). Women with high tumoral BRD4 expression in the absence of T-bet+ TILs exhibited a significantly poorer outcome (log rank test p = 0.0165) relative to other subgroups.
CONCLUSIONS: The association of BRD4 expression with T-bet+ TILs, and T-bet+ TIL-dependent disease-free survival suggests a potential link between BRD4-mediated tumor development and tumor immune surveillance, possibly through BRD4's regulation of Jagged1 signaling pathways. Further understanding BRD4's role in different immune contexts may help to identify an appropriate subset of breast cancer patients who may benefit from BET inhibitors without the risk of diminishing the anti-tumoral immune activity.

Hartana CA, Ahlén Bergman E, Broomé A, et al.
Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer.
Clin Exp Immunol. 2018; 194(1):39-53 [PubMed] Free Access to Full Article Related Publications
Tissue-resident memory T (T

Hartana CA, Ahlén Bergman E, Zirakzadeh AA, et al.
Urothelial bladder cancer may suppress perforin expression in CD8+ T cells by an ICAM-1/TGFβ2 mediated pathway.
PLoS One. 2018; 13(7):e0200079 [PubMed] Free Access to Full Article Related Publications
The immune system plays a significant role in urothelial bladder cancer (UBC) progression, with CD8+ T cells being capable to directly kill tumor cells using perforin and granzymes. However, tumors avoid immune recognition by escape mechanisms. In this study, we aim to demonstrate tumor immune escape mechanisms that suppress CD8+ T cells cytotoxicity. 42 patients diagnosed with UBC were recruited. CD8+ T cells from peripheral blood (PB), sentinel nodes (SN), and tumor were analyzed in steady state and in vitro-stimulated conditions by flow cytometry, RT-qPCR, and ELISA. Mass spectrometry (MS) was used for identification of proteins from UBC cell line culture supernatants. Perforin was surprisingly found to be low in CD8+ T cells from SN, marked by 1.8-fold decrease of PRF1 expression, with maintained expression of granzyme B. The majority of perforin-deficient CD8+ T cells are effector memory T (TEM) cells with exhausted Tc2 cell phenotype, judged by the presence of PD-1 and GATA-3. Consequently, perforin-deficient CD8+ T cells from SN are low in T-bet expression. Supernatant from muscle invasive UBC induces perforin deficiency, a mechanism identified by MS where ICAM-1 and TGFβ2 signaling were causatively validated to decrease perforin expression in vitro. Thus, we demonstrate a novel tumor escape suppressing perforin expression in CD8+ T cells mediated by ICAM-1 and TGFβ2, which can be targeted in combination for cancer immunotherapy.

Gacerez AT, Sentman CL
T-bet promotes potent antitumor activity of CD4
Cancer Gene Ther. 2018; 25(5-6):117-128 [PubMed] Free Access to Full Article Related Publications
Chimeric antigen receptor (CAR) therapy has shown promise against B cell malignancies in the clinic. However, limited success in patients with solid tumors has prompted the development of new CAR strategies. In this study, a B7H6-specific CAR was combined with different variants of T-bet, a transcription factor that acts as the master regulator to induce a Th1 phenotype in CD4

Bae J, Hideshima T, Tai YT, et al.
Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors.
Leukemia. 2018; 32(9):1932-1947 [PubMed] Free Access to Full Article Related Publications
Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138

Wang P, Huang B, Gao Y, et al.
Cell Immunol. 2018; 325:48-55 [PubMed] Related Publications

Chmielewski M, Abken H
CAR T Cells Releasing IL-18 Convert to T-Bet
Cell Rep. 2017; 21(11):3205-3219 [PubMed] Related Publications
Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bet

Zhang W, Pan Y, Gou P, et al.
Effect of xanthohumol on Th1/Th2 balance in a breast cancer mouse model.
Oncol Rep. 2018; 39(1):280-288 [PubMed] Related Publications
Xanthohumol (XN), a prenylflavonoid found in the hop plant, Humulus lupulus, exhibits a variety of biological activities. Numerous studies have reported that XN inhibits the growth of many types of cancer cells, but the effects of XN on tumor immunity have not yet been studied. We explored the effect of XN on Th1/Th2 balance and the underlying mechanism based on a BALB/c-4T1 breast cancer mouse model. The results showed that XN significantly slowed down tumor growth and inhibited expression of antitumor proliferation protein Ki-67 as well as breast cancer-specific marker cancer antigen 15-3 (CA15-3). Flow cytometric analysis revealed that XN enhanced the secretion of perforin, granzyme B and increased the ratio of CD8+/CD25+. ELISA analysis of cytokine results demonstrated that XN obviously upregulated Th1 cytokines, while downregulated Th2 cytokines. Th1/Th2 ratio analysis by flow cytometry illustrated that XN regulated the balance drift to Th1 polarization. Western blotting and immunohistochemistry (IHC) results manifested that XN induced expression of T-bet, a Th1-specific transcription factor. Furthermore, we found that XN significantly promoted the phosphorylation of signal transducer and activator of transcription (STAT)4. Our results demonstrated that XN promoted Th1/Th2 balance towards Th1 polarization, and STAT4 may play a positive role in the regulation of Th1/Th2 cytokines by XN.

Yao K, Peng C, Zhang Y, et al.
RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth.
Proc Natl Acad Sci U S A. 2017; 114(48):12791-12796 [PubMed] Free Access to Full Article Related Publications
Metastasis is a major cause of cancer-related deaths. Approximately 80% of patients with colorectal cancer develop liver metastasis and 20% develop lung metastasis. We found that at different stages of colon cancer, IFNγ secretion from peripheral blood mononuclear cells was decreased compared with healthy controls. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their roles in this observed IFNγ decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice revealed significantly lower levels of IFNγ in the RSK2 KO mice compared with the WT mice. Since IFNγ is a component of immunity, which contributes to protection against metastatic carcinomas, we conducted a colon cancer liver metastasis experiment. We found significantly greater metastasis in RSK2 KO mice compared with WT mice. Transcription factor T-bet can directly activate

Stromnes IM, Hulbert A, Pierce RH, et al.
T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma.
Cancer Immunol Res. 2017; 5(11):978-991 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to most therapies, including immune checkpoint blockade. To elucidate mechanisms of immunotherapy resistance, we assessed immune parameters in resected human PDA. We demonstrate significant interpatient variability in T-cell number, localization, and phenotype. CD8

Bianco TM, Abdalla DR, Desidério CS, et al.
The influence of physical activity in the anti-tumor immune response in experimental breast tumor.
Immunol Lett. 2017; 190:148-158 [PubMed] Related Publications
This study aimed to investigate the influence of physical activity in innate immunity to conduce to an effective antitumoral immune response analyzing the phenotype and activation status of infiltrating cells. We analysed the intracellular cytokines and the transcription factors of tumor infiltrating lymphocytes (TILS) and spleen leukocytes. The Nos2 gene expression was evaluated in spleen cells and futhermore the ROS production was measured and spleen cells; another cell evaluated was dendritic cells (TIDCs), their cytokines expression and membrane molecules; finally to understood the results obtained, we analysed the dendritic cells obtained from bone marrow. Were used female Balb/c mice divided into 4 groups: two controls without tumor, sedentary (GI) and trained (GII) and two groups with tumor, sedentary (GIII) or trained (GIV). The physical activity (PA) was realized acoording swimming protocol. Tumor was induced by injection of 4T1 cells. All experiments were performed in biological triplicate. After the experimental period, the tumor was removed and the cells were identified by flow cytometry with labeling to CD4, CD8, CD11c, CD11b, CD80, CD86 and Ia, and intracelular staining IL-10, IL-12, TNF-α, IFN-γ, IL-17, Tbet, GATA3, RORγt and FoxP3. The bone marrow of the animals was obtained to analyse the derivated DCs by flow cytometry and culture cells to obtain the supernatant to measure the cytokines. Our results demonstrated that the PA inhibit the tumoral growth although not to change the number of TILS, but reduced expression of GATA-3, ROR-γT, related with poor prognosis, and TNF-α intracellular; however occur one significantly reduction in TIDCS, but these cells expressed more co-stimulatory and presentation molecules. Furthermore, we observed that the induced PA stimulated the gene expression of Tbet and the production of inflammatory cytokines suggesting an increase of Th1 systemic response. The results evaluating the systemic influence in DCs showed that the PA improve significantly the number of those cells in bone marrow as well the number of co-stimulatory molecules. Therefore, we could conclude that PA influence the innate immunity by interfering to promote in process of maturation of DCs both in tumor and systemically, that by its turn promote a modification in acquired immune cells, representing by T helper to induce an important alteration transcription factors that are responsible to maintain a suppressive microenviroment, and thereby, allowing the latter cells can thus activate antitumor immune response. The PA was able improve the Th1 systemic response by enhance to Tbet gene expression, promote a slightly increased of Th1-type cytokines and decrease Gata3 and Foxp3 gene expression in which can inhibit the Th1 immune response.

Xu C, Zhang Y, Rolfe PA, et al.
Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models.
Clin Cancer Res. 2017; 23(19):5869-5880 [PubMed] Related Publications

Chew V, Lai L, Pan L, et al.
Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses.
Proc Natl Acad Sci U S A. 2017; 114(29):E5900-E5909 [PubMed] Free Access to Full Article Related Publications
The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8

Bhat S, Gardi N, Hake S, et al.
Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients.
J Cancer Res Clin Oncol. 2017; 143(9):1745-1756 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Pro-inflammatory cytokines such as Interleukin-17A (IL17A) and Interleukin-32 (IL32), known to enhance natural killer and T cell responses, are also elevated in human malignancies and linked to poor clinical outcomes. To address this paradox, we evaluated relation between IL17A and IL32 expression and other inflammation- and T cell response-associated genes in breast tumors.
METHODS: TaqMan-based gene expression analysis was carried out in seventy-eight breast tumors. The association between IL17A and IL32 transcript levels and T cell response genes, ER status as well as lymph node status was also examined in breast tumors from TCGA dataset.
RESULTS: IL17A expression was detected in 32.7% ER-positive and 84.6% ER-negative tumors, with higher expression in the latter group (26.2 vs 7.1-fold, p < 0.01). ER-negative tumors also showed higher expression of IL32 as opposed to ER-positive tumors (8.7 vs 2.5-fold, p < 0.01). Expression of both IL17A and IL32 genes positively correlated with CCL5, GNLY, TBX21, IL21 and IL23 transcript levels (p < 0.01). Amongst ER-positive tumors, higher IL32 expression significantly correlated with lymph node metastases (p < 0.05). Conversely, in ER-negative subtype, high IL17A and IL32 expression was seen in patients with negative lymph node status (p < 0.05). Tumors with high IL32 and IL17A expression showed higher expression of TH1 response genes studied, an observation validated by similar analysis in the TCGA breast tumors (n=1041). Of note, these tumors were characterized by low expression of a potentially immunosuppressive isoform of IL32 (IL32γ).
CONCLUSION: These results suggest that high expression of both IL17A and IL32 leads to enhancement of T cell responses. Our study, thus, provides basis for the emergence of strong T cell responses in an inflammatory milieu that have been shown to be associated with better prognosis in ER-negative breast cancer.

Rutkowski J, Ślebioda T, Kmieć Z, Zaucha R
Changes in systemic immune response after stereotactic ablative radiotherapy. Preliminary results of a prospective study in patients with early lung cancer.
Pol Arch Intern Med. 2017; 127(4):245-253 [PubMed] Related Publications
INTRODUCTION    Non‑small cell lung cancer (NSCLC) is the most common lung tumor. Conventional conservative treatment in medically inoperable patients with early stage NSCLC has poor outcome. To improve treatment efficacy, stereotactic ablative radiotherapy (SABR) has been developed, which enables the delivery of high‑dose radiation to the tumor. OBJECTIVES    This prospective study was conducted to test the hypothesis that a sudden death of cancer cells after SABR may lead to changes in systemic immune response.  PATIENTS AND METHODS    We enrolled 89 treatment‑naive patients with stage T1/2aN0 NSCLC. All patients received SABR, in accordance with treatment standards at our department. Blood samples were collected 3 times: before treatment (n = 89), and then at 2 (n = 86) and 12 weeks (n = 75) after treatment completion to assess the proportion of CD4(+) and CD8(+) T cells, and the expression of T‑lymphocyte transcription factors: T‑bet, GATA‑3, ROR‑γt, and FoxP3. Serum C‑reactive protein (CRP) levels, absolute neutrophil count (ANC), absolute lymphocyte count, and white blood cell (WBC) count were measured to exclude the impact of nonspecific inflammatory reaction. The expression levels of lymphocyte antigens were measured by flow cytometry. RESULTS    Serum CRP levels, ANC, and WBC count remained stable during the study. We observed slight lymphopenia, which correlated with irradiated lung volume. After SABR, the proportion of CD8(+), CD4(+), as well as the proportion of CD4(+) T cells expressing GATA‑3(+), T‑bet(+), or ROR‑γt(+) increased, while the number of CD4(+)FoxP3(+) cells (specific for regulatory T cells) decreased. CONCLUSIONS    Our findings may suggest that SABR enhances the systemic immune response by increasing the proportion of proinflammatory T‑cell subpopulations.

Wang Z, Yin N, Zhang Z, et al.
Upregulation of T-cell Immunoglobulin and Mucin-Domain Containing-3 (Tim-3) in Monocytes/Macrophages Associates with Gastric Cancer Progression.
Immunol Invest. 2017; 46(2):134-148 [PubMed] Related Publications
T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) is an important immune regulatory molecule in cancer immune system. However, expression and function of Tim-3 in monocytes/macrophages in cancer progression mainly remain unclear. In this study, we analyzed Tim-3 levels in peripheral blood mononuclear cells (PBMCs) from 62 gastric cancer patients and 45 healthy controls using flow cytometry and then associated Tim-3 levels with clinical pathological data from patients. We found Tim-3 level was significantly upregulated in monocytes from gastric cancer patients compared with those from healthy controls, and that upregulated Tim-3 levels associated with depth of tumor invasion and tumor lymph node metastasis and advanced clinical stages of gastric cancer patients. Furthermore, tumor-bearing mouse experiments revealed that Tim-3 level on monocytes/macrophages associated with xenograft formation and growth. In addition, culture of monocytes from healthy controls with gastric cancer cell-conditioned medium upregulated Tim-3 expression, but IL-10, TNF-α, IFN-γ, or GM-CSF treatment or T-bet, Eomes, and T-bet/Eomes double gene knockout did not affect Tim-3 levels in blood monocytes/macrophages from human or mouse, respectively. Gal-9/Tim-3 signal was able to significantly stimulate monocyte to secrete IL-6, IL-8, and IL-10, but not IL-1β, IL-12p70, or TNF-α in presence of LPS. In conclusion, our study demonstrated that Tim-3 expressed by monocyte/macrophages might be an important mechanism in gastric cancer progression.

Zhang G, Liu H, Huang J, et al.
TREM-1low is a novel characteristic for tumor-associated macrophages in lung cancer.
Oncotarget. 2016; 7(26):40508-40517 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To explore the expression feature and biological functions of TREM-1 on tumor-associated macrophages (TAMs) in lung cancer.
RESULTS: The levels of TREM-1 on tissue-infiltrating monocytes/macrophage from tumor nest were significantly lower than those from nonturmor tissue or peripheral blood samples. Clinical analysis indicated that the levels of TREM-1-related TAMs were significantly decreased during cancer stages progression. The tumor-bearing mouse model further confirmed that the expression of TREM-1 on TAMs was significantly decreased with tumor growth. In addition, we found the activation of TREM-1 could significantly enhance the secretion of IL-1β by TAM in vitro. Furthermore, T-bet but not Eomes was found to be the key transcription factor for the TREM-1 expression on monocytes/macrophage.
METHODS: A total of 40 patients with non-small cell lung cancer (NSCLC) were enrolled in this study. The expression characteristics of TREM-1 in blood and tissue-infiltrating monocytes/macrophage were examined by flow cytometry analysis. After the treatment of TREM-1 antibody, which is an agonist of TREM-1, cytokines secreted by TAM were then analyzed. In LLC-tumor bearing mouse model, we further investigated the dynamic expression feature of TREM-1 on macrophage with tumor growth. Moreover, we explored the transcription factor for regulating TREM-1 expression on monocyes/macrophage with wildtype, T-bet Ko or Eomes Ko mice.
CONCLUSION: The levels of TREM-1 were remarkably decreased during tumor progression. The low expression level of TREM-1 might be a characteristic for TAMs in lung cancer.

Zhang Z, Liang L, Li D, et al.
Hypermethylation of PRDM1/Blimp-1 promoter in extranodal NK/T-cell lymphoma, nasal type: an evidence of predominant role in its downregulation.
Hematol Oncol. 2017; 35(4):645-654 [PubMed] Related Publications
The loss of PRDM1 expression is common in extranodal NK/T-cell lymphoma, nasal type (EN-NK/T-NT), but the role of promoter methylation in silencing PRDM1 expression remains unclear. Hence, we performed pyrosequencing analysis to evaluate the promoter methylation of PRDM1 gene in vivo and in vitro, to analyze the association between methylation and its expression, and to assess cellular effects of PRDM1 reexpression. The promoter hypermethylation of PRDM1 gene was detected in 11 of 25 EN-NK/T-NT cases (44.0%) and NK92 and NKL cells. The promoter hypermethylation of PRDM1 was significantly correlated with PRDM1 expression in vivo and in vitro, predominantly contributing to the loss of PRDM1 expression compared with genetic deletion and aberrant expression of miR-223 in EN-NK/T-NT. PRDM1 expression was significantly restored by demethylation treatment, which induced cell proliferation suppression, cell cycle arrest, and apoptosis increase. We also found that PRDM1 reexpression could downregulate the expression of Ets-1, T-bet, granzyme B, and c-myc. Our findings demonstrated that the promoter hypermethylation of PRDM1 harbored a predominant role in the downregulation of PRDM1 expression, significantly affecting the biological behavior of tumor cells in EN-NK/T-NT.

Wang R, Xu A, Zhang X, et al.
Novel exosome-targeted T-cell-based vaccine counteracts T-cell anergy and converts CTL exhaustion in chronic infection via CD40L signaling through the mTORC1 pathway.
Cell Mol Immunol. 2017; 14(6):529-545 [PubMed] Free Access to Full Article Related Publications

Bahria-Sediki IB, Yousfi N, Paul C, et al.
Clinical significance of T-bet, GATA-3, and Bcl-6 transcription factor expression in bladder carcinoma.
J Transl Med. 2016; 14(1):144 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The aim of this study was to investigate the clinical significance of three immune cell-related transcription factors, T-bet, GATA-3 and Bcl-6 in bladder cancer in Tunisian patients.
METHODS: Expression of T-bet, GATA-3 and Bcl-6 genes was assessed using RT-qPCR in 65 bladder cancers from patients: 32 being diagnosed as low- and medium-grade, 31 as high-grade, 25 as muscle invasive stage and 39 as non-muscle invasive stage. Gene expression was statistically correlated according to the grade, the stage, tobacco consumption, the BCG response and disease severity.
RESULTS: T-bet levels in patients with high-grade bladder cancer were significantly elevated compared to patients with low- or medium-grade bladder cancer (p = 0.005). In invasive carcinoma (T2-T4), the T-bet levels were significantly higher than in superficial non-invasive bladder tumors (Tis, Ta, and T1) (p = 0.02). However, T-bet is predictive of the response to BCG. Its expression is high in good responders to BCG (p = 0.02). In contrast, the expression of GATA-3 and Bcl-6 in non-invasive carcinoma (p = 0.008 and p = 0.0003) and in patients with low- and medium-grade cancers (p = 0.001 and p < 0.0001) is significantly higher than in invasive bladder tumors and in patients with high-grade bladder carcinoma, respectively. In addition, heavy smokers, whose tumors express low levels of GATA-3 and Bcl-6, are poor responders to BCG (p = 0.01 and p = 0.03). Finally, better patient survival correlated with GATA-3 (p = 0.04) and Bcl-6 (p = 0.04) but not T-bet expression.
CONCLUSIONS: Our results suggest that T-bet expression in bladder tumors could be a positive prognostic indicator of BCG therapy, even if high levels are found in high-grade and stage of the disease. However, GATA-3 and Bcl-6 expression could be considered as predictive factors for good patient survival.

Webb JR, Milne K, Kroeger DR, Nelson BH
PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer.
Gynecol Oncol. 2016; 141(2):293-302 [PubMed] Related Publications
OBJECTIVE: As a negative regulator of T cells, Programmed Death Ligand 1 (PD-L1) is both an indicator and inhibitor of anti-tumor immune responses, which has led to confusion about its prognostic significance. We investigated the primary source of PD-L1 expression in epithelial ovarian cancer and its relationship to tumor-infiltrating lymphocytes (TIL) and associated gene products.
METHODS: Tissue microarrays containing high-grade serous carcinomas (HGSC) and endometrioid, clear cell and mucinous ovarian cancers from optimally debulked patients were assessed by immunohistochemistry for expression of PD-L1 and other markers (CD68, CD3, CD8, PD-1, CD103, FoxP3 and CD25). The Cancer Genome Atlas was interrogated for associations between PD-L1 expression and immune-related transcriptional and genomic features of HGSC.
RESULTS: PD-L1 was primarily expressed by tumor-associated CD68(+) macrophages rather than tumor cells. PD-L1(+) cells frequently co-localized with CD8, CD4 and PD-1(+) TIL, CD25(+)FoxP3(+) Tregs, and other TIL subsets. PD-L1(+) cells were prognostically favorable in HGSC. Moreover, the presence of both PD-L1(+) cells and CD8 TIL was associated with better prognosis than CD8 TIL alone. PD-L1 gene expression was independent of BRCA status. At the transcriptional level, PD-L1 was associated with both cytolytic (granzyme B, T-bet and IFN-γ) and suppressive (PD-1, CTLA-4, LAG3 and IDO-1) gene products.
CONCLUSIONS: PD-L1 is primarily expressed by macrophages in ovarian cancer and is strongly associated with both cytolytic and regulatory TIL subsets, resulting in a net positive association with survival. Tumors containing PD-L1(+) macrophages appear caught in an immunological stalemate that may require multi-pronged immunotherapy to alleviate.

Dielmann A, Letsch A, Nonnenmacher A, et al.
Favorable prognostic influence of T-box transcription factor Eomesodermin in metastatic renal cell cancer patients.
Cancer Immunol Immunother. 2016; 65(2):181-92 [PubMed] Related Publications
T-box transcription factors, T-box expressed in T cells (T-bet) encoded by Tbx21 and Eomesodermin (Eomes), drive the differentiation of effector/memory T cell lineages and NK cells. The aim of the study was to determine the prognostic influence of the expression of these transcription factors in peripheral blood (pB) in a cohort of 41 metastatic (m) RCC patients before receiving sorafenib treatment and to analyze their association with the immunophenotype in pB. In contrast to Tbx21, in the multivariate analysis including clinical features, Eomes mRNA expression was identified as an independent good prognostic factor for progression-free survival (PFS, p = 0.042) and overall survival (OS, p = 0.001) in addition to a favorable ECOG performance status (p = 0.01 and p = 0.008, respectively). Eomes expression correlated positively not only with expression of Tbx21 and TGFβ1 mRNA, but also with mRNA expression of the activation marker ICOS, and with in vivo activated HLA-DR(+) T cells. Eomes expression was negatively associated with TNFα-producing T cells. On protein level, Eomes was mainly expressed by CD56(+)CD3(-) NK cells in pB. In conclusion, we identified a higher Eomes mRNA expression as an independent good prognostic factor for OS and PFS in mRCC patients treated with sorafenib.

Fukuoka N, Harada M, Nishida A, et al.
Eomesodermin promotes interferon-γ expression and binds to multiple conserved noncoding sequences across the Ifng locus in mouse thymoma cell lines.
Genes Cells. 2016; 21(2):146-62 [PubMed] Related Publications
The T-box transcription factors T-bet and eomesodermin (Eomes) have been shown to regulate the lineage-specific expression of interferon-γ (IFN-γ). However, in contrast to T-bet, the role of Eomes in the expression of IFN-γ remains unclear. In this study, we investigated the Eomes-dependent expression of IFN-γ in the mouse thymoma BW5147 and EL4 cells, which do not express T-bet or Eomes. The ectopic expression of Eomes induced BW5147 and EL4 cells to produce IFN-γ in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin (IM). In BW5147 cells, Eomes augmented luciferase activity driven by the Ifng promoter encoding from -2500 to +113 bp; however, it was not increased by a stimulation with PMA and IM. A chromatin immunoprecipitation assay showed that Eomes bound to the Ifng promoter and conserved noncoding sequence (CNS) -22 kb across the Ifng locus with high efficacy in BW5147 cells. Moreover, Eomes increased permissive histone modifications in the Ifng promoter and multiple CNSs. The stimulation with PMA and IM greatly augmented Eomes binding to CNS-54, CNS-34, CNS+19 and CNS+30, which was inhibited by FK506. These results indicated that Eomes bound to the Ifng promoter and multiple CNSs in stimulation-dependent and stimulation-independent manners.

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