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3D genome organization by CTCF prevents exTreg differentiation to control autoimmunity peripheral tolerance and immunotherapy outcomes [bulkRNAseq_ATACseq_CUT_Tag]

ABSTRACT: Regulatory T cells (Tregs) can undergo transformation into exTregs by downregulating Foxp3 expression, yet the underlying mechanisms and functional implications remain incompletely understood (1, 2). Here, we show that PD-1 blockade induces significant alterations in chromatin accessibility at CTCF binding sites within tumor-infiltrating Tregs. CTCF plays a crucial role in maintaining Treg identity and preventing autoimmune disorders in mice through the three-dimensional organization of key genes regulating Treg stability. Moreover, acute deletion of Treg-specific CTCF enhances T cell responses and promotes the differentiation of CD40L-expressing exTregs within tumors, without disrupting overall immune homeostasis in murine models. The single-cell T cell receptor sequencing analysis of colitis tissues from melanoma patients treated with anti-PD-1 and anti-CTLA-4 antibodies reveals a notable emergence of exTregs, elucidating the paradoxical increase in both Tregs and cytotoxic CD8+ T cells (3) (3, 4). Our findings underscore the therapeutic potential of manipulating exTreg differentiation to enhance cancer immunotherapy and mitigate associated adverse effects.

ORGANISM(S): Mus musculus

PROVIDER: GSE274542 | GEO | 2025/09/30

REPOSITORIES: GEO

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3D genome organization by CTCF prevents exTreg differentiation to control autoimmunity peripheral tolerance and immunotherapy outcomes [Hi-C]

Project description:Regulatory T cells (Tregs) can undergo transformation into exTregs by downregulating Foxp3 expression, yet the underlying mechanisms and functional implications remain incompletely understood (1, 2). Here, we show that PD-1 blockade induces significant alterations in chromatin accessibility at CTCF binding sites within tumor-infiltrating Tregs. CTCF plays a crucial role in maintaining Treg identity and preventing autoimmune disorders in mice through the three-dimensional organization of key genes regulating Treg stability. Moreover, acute deletion of Treg-specific CTCF enhances T cell responses and promotes the differentiation of CD40L-expressing exTregs within tumors, without disrupting overall immune homeostasis in murine models. The single-cell T cell receptor sequencing analysis of colitis tissues from melanoma patients treated with anti-PD-1 and anti-CTLA-4 antibodies reveals a notable emergence of exTregs, elucidating the paradoxical increase in both Tregs and cytotoxic CD8+ T cells (3) (3, 4). Our findings underscore the therapeutic potential of manipulating exTreg differentiation to enhance cancer immunotherapy and mitigate associated adverse effects.

2025-09-30 | GSE274543 | GEO

3D genome organization by CTCF prevents exTreg differentiation to control autoimmunity peripheral tolerance and immunotherapy outcomes [scRNAseq_scTCRseq]

2025-09-30 | GSE274545 | GEO

Synergistic Role of DGKalpha and zeta in Regulatory T cell function, stability, and pathogenecity

Project description:Regulatory T cells (Tregs) actively engage in immune suppression to prevent autoimmune diseases but also inhibit anti-tumor immunity. Although Tregs express a TCR repertoire with relatively high affinities to self, they are normally quite stable and their inflammatory programs are intrinsically suppressed. We report here that diacylglycerol kinases (DGK) alpha and zeta are crucial for homeostasis, suppression of proinflammatory programs, and stability of Tregs and for enforcing their dependence on CD28 costimulatory signal. Treg-specific deficiency of both DGKa and z derails signaling, metabolic, and transcriptional programs in Tregs to cause dysregulated phenotypic and functional properties and to unleash conversion to pathogenic exTregs, especially exTreg-T follicular helper (Tfh) 2 cells, leading to uncontrolled effector T cell differentiation, deregulated germinal center B cell responses and IgG1/IgE predominant antibodies/autoantibodies, and multiorgan autoimmune diseases. Our data not only illustrate the crucial roles of DGKs in Tregs to maintain self-tolerance but also unveil a Treg-to-self-reactive-pathogenic-exTreg-Tfh-cell program that is suppressed by DGKs and that could exert broad pathogenic roles in autoimmune diseases if unchecked.

2025-08-23 | GSE276410 | GEO

Single-cell RNA-seq uncovers unique gene expression profiles in the spleen of hypoxic mice

Project description:The stability of FOXP3 expression in Tregs influences the balance between tolerance and autoimmunity. Treg cell development and function are regulated by IL-2, which binds to IL-2Rα (also called CD25). Decreased expression of CD25 (Il2ra gene) characterizes Tregs that lose FOXP3 expression (exTregs) and undergo transdifferentiation into TH17 cells. This has been established under arthritic conditions but whether this Treg transdifferenciation into exTregs occur following hypoxia exposure, it is unknown. Therefore, single-cell RNA-seq (10x Genomics) was performed using a 10X Genomics Chromium system to test the hypothesis that hypothesis that chronic hypoxia initiates Treg transcriptional reprogramming.

2024-01-16 | GSE219259 | GEO

CD49f defines a subset of dysfunctional regulatory T cells circulating in the human peripheral blood

Project description:The therapeutic use of regulatory T cells (Tregs) in patients with autoimmune disorders has been hampered by the biological variability of memory Treg populations in the peripheral blood. In this study, we reveal through a combination of quantitative proteomic, multiparametric flow cytometry, RNA-seq data analysis and functional assays, that CD49f is heterogeneously expressed among human Tregs and impacts their immunomodulatory function. High expression of CD49f defines a subset of dysfunctional Tregs in the human blood characterized by a Th17-like phenotype and impaired suppressive capacity. CD49f is similarly distributed between naïve and memory Tregs and impacts the expression of CD39, CTLA-4, FoxP3 and CCR6 specifically in the memory compartment. Accumulation of CD49f high memory Tregs in the blood of ulcerative colitis patients correlates with disease severity. Our results highlight important considerations for Treg immunotherapy design in patients with inflammatory bowel disease which could possibly extend to other autoimmune disorders.

2021-08-06 | PXD022095 | Pride

Differential roles of TSLP and IL-33 in regulation of Treg cells in progression of colorectal cancer

Project description:Recruitment of regulatory T cells (Tregs) to tumors is a hallmark of cancer progression. However, the role of epithelial cell-derived cytokines in regulation of Treg cells in colorectal cancers is not fully understood. We found a subset of Tregs co-expressing the receptors for thymic stromal lymphopoietin (TSLP) and IL-33 (TSLPR+ST2+ Tregs) was increased in colorectal tumors in humans and mice. This Treg subset expressed high levels of CTLA-4 and PD-1, and TSLPR signaling regulated the expression of CTLA-4 and number of TSLPR+ST2+ Tregs. Treg-specfic deletion of TSLPR resulted in a reduction in tumor number and size, with concomitant increase of Th1 cells in tumors. Similarly, blockade of TSLP effectively inhibited progression of colorectal tumors. On the other hand, TSLPR-ST2+ Tregs highly express Tgfb1 and Pdcd,1 which have been shown to suppress CD8+ T cell immune responses. Collectively, TSLP and IL-33 differentially regulate subsets of Tregs in the progression of colorectal tumor. These data suggest that TSLPR+ST2+ Treg cells are potentially a biomarker, and a therapeutic target for CRC.

2021-12-22 | GSE173124 | GEO

Anti-VEGF treatment enhances antitumor responses by targeting regulatory T cells

Project description:Cholangiocarcinoma (CCA) shows limited response to systemic treatments including immunotherapy. We initiated an open-label phase II clinical trial testing bevacizumab (anti-VEGF-A) plus tremelimumab (anti-CTLA-4) and durvalumab (anti-PD-L1) in patients with primary liver cancer. Exceptional responses were observed in patients with CCA that were accompanied with moderate to severe, yet manageable immune-related events in the majority of patients. Correlative studies using paired PBMC and serum samples demonstrated a proinflammatory cytokine profile, reinvigoration of precursor exhausted CD8+ T cells, and expansion of regulatory T cell and non-classical monocyte subsets. We utilized subcutaneous, orthotopic as well as plasmid-induced murine CCA models to better understand how anti-VEGF-A enhances anti-tumor immunity induced by anti-CTLA4 plus anti-PD-L1. We describe a novel multi-modal mechanism of how anti-VEGF-A therapy enhances immune checkpoint inhibitor-induced immune responses. The treatment effect was dependent on an increase in tumor infiltrating B cells and IL-12 causing Treg rewiring towards fragile and unstable states. Using a mouse model that genetically ablates VEGFR2 expression on Tregs, we show that the VEGF /VEGFR2 axis on Tregs contributes to the pro-tumoral function of Tregs and supports tumor progression in a syngeneic CCA model. This study provides clinical evidence that simultaneously targeting three immunosuppressive axes, namely VEGF-A, CTLA-4 and PD-L1, can elicit strong anti-tumor immunity to potentiate CCA regression and merits broader evaluation in other cancers.

2025-03-14 | GSE249974 | GEO

Identification of human exTregs as CD16+CD56+ cytotoxic CD4+ T cells.

Project description:In chronic inflammatory diseases with an autoimmune component like atherosclerosis, some regulatory T cells (Tregs) lose their regulatory function and become exTregs. The present study was designed to identify surface markers specific of human exTregs, using an integrated approach from sorted mouse exTregs bulk RNA-Seq to human scRNA-Seq with CITE-Seq, to sort human exTregs and characterize them by transcriptome and function. We crossed inducible Treg lineage tracker mice (FoxP3-eGFP-Cre-ERT2 ROSA26CAG-fl-stop-fl-tdTomato) to atherosclerosis-prone Apoe -/- mice, sorted Tregs and exTregs from lymph nodes and spleens of replicate mice and determined their transcriptomes by bulk RNA sequencing (RNA-Seq). A support vector machine (SVM) approach identified the leading signature genes for exTregs as CST7, NKG7, GZMA, PRF1, TBX21 and CCL4. Projecting these genes onto feature maps of human PBMC single cell (sc)RNA-Seq with CITE-Seq from 61 subjects with and without atherosclerosis showed that CST7, NKG7, GZMA, PRF1, TBX21 and CCL4 mapped to CD4 T cells that expressed CD56 and CD16. This finding was validated in a second, independent scRNA- and CITE-Seq dataset. Even in healthy volunteers, a subpopulation of CD4 T cells expressed both CD56 and CD16. Bulk RNA-Seq identified these cells as cytotoxic CD4 T cells, which was functionally confirmed in a cell killing assay. DNA sequencing for TCRβ showed clonal expansion of Treg CDR3 sequences in CD16 + CD56 + exTregs. Taken together, we identify mouse and human exTregs as cytotoxic CD4 T cells.

2023-07-25 | GSE217010 | GEO

Intratumoral anti-CTLA-4 delivery by an oncolytic Vaccinia virotherapy virus elicits CD8+ T cell immunity and synergizes with anti-PD-1 to reject “cold” tumors

Project description:CTLA-4 is a clinically validated antibody target for cancer immunotherapy. Toxicity, which is linked to efficacy in available anti-CTLA-4 regimens has, however, restricted their use and precluded full therapeutic dosing. Here we describe and preclinically characterize a potentially safe and highly efficacious strategy to target CTLA-4. Intratumoral administration of an oncolytic Vaccinia virus, engineered to encode a novel Treg depleting, checkpoint-blocking, anti-CTLA-4 antibody and GM-CSF (VVGM-aCTLA4) achieved tumor-restricted CTLA-4 receptor saturation and Treg-depletion, and regressed diverse tumors spanning inflamed to immunologically ignorant microenvironments. Critically, intratumorally “ignited” antitumor immunity translated into stronger systemic expansion of tumor-specific CD8+ T cells compared with systemic anti-CTLA-4. In a clinically relevant mouse model resistant to systemic immune checkpoint blockade, i.t. VVGM-aCTLA4 synergized with anti-PD-1 to reject “cold” tumors. Based on our established proof-of-concept, a clinical trial evaluating i.t. VVGM-aCTLA4 (BT-001) alone and in combination with anti-PD-1 in metastatic or advanced solid tumors has commenced.

2022-02-08 | GSE176052 | GEO

The immune checkpoint B7x promotes tumor-infiltrating tregs and resistance to anti-CTLA-4 therapy.

Project description:Tumor cells inhibit the anti-tumor immune response by expressing immunomodulatory factors and recruiting immunosuppressive cells to their microenvironment. Regulatory T cells (Tregs) are a population of CD4+ T cells that are commonly found in tumors, promoting a tolerogenic microenvironment and aiding in tumor immune evasion. The immune checkpoint ligand B7x is widely expressed in a broad variety of tumor types and is often associated with greater Treg infiltration, but the mechanism by which B7x promotes tumor-infiltrating Tregs is unknown. Here, we recapitulate the B7x-mediated increase in Tregs in murine tumor models and show that B7x promotes conversion of conventional CD4+ T cells into potently suppressive Tregs. We found that B7x induces global transcriptomic changes in Tregs, driving these cells to adopt an activated and suppressive phenotype. Mechanistically, B7x increased Foxp3 transcriptional expression by modulating the Akt/Foxo signaling pathway. Further, we found that expression of B7x by tumor cells reduced the efficacy of anti-CTLA-4 in syngeneic murine models in a Treg-dependent manner, but this resistance phenotype was overcome by combination anti-B7x and anti-CTLA-4 treatment. Put together, B7x mediates a novel Treg-promoting pathway within tumors and is a promising candidate for combination immunotherapy.

2022-04-02 | GSE199751 | GEO

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