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Integrated multiomics profiling identifies the differentiation program of regulatory T cells in human tumors [bulk ATAC-seq]

ABSTRACT: Regulatory T (Treg) cells suppress effective antitumor immunity in tumor-bearing hosts, thereby becoming promising targets in cancer immunotherapy. Here, we show that Treg cells in the tumor microenvironment (TME) of human lung cancers harbor a completely different open chromatin profile compared to effector T cells and peripheral Treg cells. The integrative sequencing analyses revealed that BATF, IRF4, NF-κb, and NR4A were important transcription factors for Treg cell differentiation in the TME. Particularly, BATF was identified as a key regulator, which leveraged Treg cell differentiation through epigenetically controlling activation-associated gene expression, resulting in the robustness of Treg cells in the TME. BATF deficiency in Treg cells remarkably inhibited tumor growth and high BATF expression was associated with poor prognosis in lung cancer, kidney cancer, and melanoma. Our results propose the specific chromatin remodeling and differentiation program of Treg cells in the TME, which can be applied in the development of Treg cell-targeted therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211153 | GEO | 2022/08/22

REPOSITORIES: GEO

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Integrated multiomics profiling identifies the differentiation program of regulatory T cells in human tumors [scATAC-seq]

Project description:Regulatory T (Treg) cells suppress effective antitumor immunity in tumor-bearing hosts, thereby becoming promising targets in cancer immunotherapy. Here, we show that Treg cells in the tumor microenvironment (TME) of human lung cancers harbor a completely different open chromatin profile compared to effector T cells and peripheral Treg cells. The integrative sequencing analyses revealed that BATF, IRF4, NF-κb, and NR4A were important transcription factors for Treg cell differentiation in the TME. Particularly, BATF was identified as a key regulator, which leveraged Treg cell differentiation through epigenetically controlling activation-associated gene expression, resulting in the robustness of Treg cells in the TME. BATF deficiency in Treg cells remarkably inhibited tumor growth and high BATF expression was associated with poor prognosis in lung cancer, kidney cancer, and melanoma. Our results propose the specific chromatin remodeling and differentiation program of Treg cells in the TME, which can be applied in the development of Treg cell-targeted therapies.

2022-08-22 | GSE211087 | GEO

Integrated multiomics profiling identifies the differentiation program of regulatory T cells in human tumors [scRNA-seq]

2022-08-22 | GSE211068 | GEO

Integrated multiomics profiling identifies the differentiation program of regulatory T cells in human tumors [bulk RNA-seq]

2022-08-22 | GSE211044 | GEO

Integrated multiomics profiling identifies the differentiation program of regulatory T cells in human tumors [mouse bulk ATAC-seq]

2022-08-22 | GSE211062 | GEO

Gene expression profiles of wild type and Nr4a-triple knockout (Nr4a-TKO) Tnaive and iTreg 3 h

Project description:In this study, we investigated the roles of Nr4a family transcription factors in Th and Treg cell differentiation from Tnaive cells. Nr4a factors were found to promote Treg cell differentiation and repress Th1 and Th2 differentiation. During Treg cell differentiation, all Nr4a factors are transiently induced in Tnaive cells immediately after TCR stimulation, whereby they mediate epigenetic changes directly or by cooperating with other transcription factors. To reveal Nr4a factors' mediated transcrptional events, we analyzed gene expression of wild type and Nr4a-tripple knockout (Nr4a-TKO) Tnaive and iTreg cells by microarray analysis.

2020-07-08 | GSE153926 | GEO

Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells

Project description:Studies over the past decade characterized murine regulatory T cells (Tregs) with the capacity to promote tissue regeneration. In humans, such a population of tissue-repair Treg cells has not been discovered yet. Using single-cell chromatin accessibility profiles of murine and human tissue Treg cells, we defined a species-conserved and microbiota-independent repair Treg signature, with a prevailing footprint of the transcription factor BATF. Combining this signature with gene expression profiling and TCR fate mapping, we identified a population of tissue-like Treg cells in peripheral blood, characterized by the expression of BATF, CCR8 and HLA-DR. Human BATF+CCR8+ Treg cells from normal skin and adipose tissue shared features with tumor-resident Treg and tissue T-follicular helper (Tfh) cells. Inducing a Tfh-like differentiation program in naive Treg cells partially recapitulated human tissue Treg characteristics, including enhanced wound healing potential

| EGAS00001004900 | EGA

Gene expression profiles of wild type, Nr4a-triple knockout (Nr4a-TKO), and Foxp3-KO iTreg 24 h

Project description:In this study, we investigated the roles of Nr4a family transcription factors in Th and Treg cell differentiation from Tnaive cells. Nr4a factors were found to promote Treg cell differentiation and repress Th1 and Th2 differentiation. During Treg cell differentiation, all Nr4a factors are transiently induced in Tnaive cells immediately after TCR stimulation, whereby they mediate epigenetic changes directly or by cooperating with other transcription factors. To reveal Nr4a factors' mediated transcrptional events, we analyzed gene expression of wild type and Nr4a1,a2,a3-tripple knockout (Nr4a-TKO) iTreg cells by microarray analysis.

2020-07-08 | GSE153927 | GEO

Comparison of mRNA expression pattern between wild-type regulatory T (Treg) cells and Nr4a-deficient Treg cells

Project description:Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many aspects of immune system physiology and pathophysiology. Treg cells are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory cytokine genes. However, the molecular mechanisms that establish and/or maintain such gene regulation in Treg cells remain largely unknown. We recently reported that Nr4a family nuclear orphan receptors are essential for the development of Treg cells. The fact that Treg cells maintain high levels of expression of all Nr4a family components suggests that they may also play critical roles beyond Treg cell development. Thus, we compared mRNA expression pattern between wild-type Treg cells and Nr4a-deficietn Treg cells. As a result, we found that expression of 'Treg-signature genes' were globally down regulated in Nr4a-deficient Treg cells. mRNA from wild-type and Nr4a-deficient Treg cells were analyzed.

2015-06-27 | E-GEOD-70306 | biostudies-arrayexpress

Involvement of Nr4a in a Treg-specific transcriptional program and suppression ofM-cM-^@M-^@Th2/Tfh response

Project description:Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many aspects of immune system physiology and pathophysiology. Treg cells are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory cytokine genes. However, the molecular mechanisms that establish and/or maintain such gene regulation in Treg cells remain largely unknown. We recently reported that Nr4a family nuclear orphan receptors are essential for the development of Treg cells. The fact that Treg cells maintain high levels of expression of all Nr4a family components suggests that they may also play critical roles beyond Treg cell development. Here, we show that Nr4a factors are essential for maintaining Treg-specific gene expression programs, mediating two defined characteristics of Treg cells: lineage stability and suppressive activity. A compound knockout mouse strain in which all Nr4a genes were specifically deleted in Treg cells developed systemic immunopathology with accelerated Th2/Tfh/IgE reactions. Treg cells in these mice showed global reduction of 'Treg signature' gene expression, including Foxp3, Il2ra and Ikzf4. These findings demonstrate that Nr4a controls a genetic program indispensable for Treg cell maintenance and function. mRNA from wild-type and Nr4a-deficient Treg cells were analyzed.

2013-12-23 | E-GEOD-53574 | biostudies-arrayexpress

Lineage tracing reveals the pro-tumorigenic niche role of tissue resident macrophages in early lung cancer lesions [scRNA-seq]

Project description:To explore the diversity of the MF compartment in human non-small cell lung carcinoma lesions (NSCLC), we first performed an unbiased single cell RNA-sequencing (scRNAseq) analysis of CD45+ tumor-associated leukocytes. We identified distinct MF populations enriched in human tumors and found related MF phenotypes in mouse lung tumors. Using lineage-tracing, we discovered these discrete MF populations differ in origin and have a distinct temporal and spatial distribution in the TME. Longitudinal tumor imaging revealed that upon tumor cell seeding, TRMF accumulate in proximity to tumor cells to promote tumor cell epithelial mesenchymal transition and invasiveness, while also inducing a potent T regulatory (Treg) response that protects tumor cells from adaptive immunity. TRMF depletion prior to tumor implantation, while sparing Mo-MF, did not affect tumor cell seeding but significantly reduced Treg numbers, dampened the Treg regulatory program, promoted the accumulation of CD8+ T cells in tumor lesions, and reduced tumor invasiveness and growth. During tumor growth, TRMF redistributed at the periphery of the TME, which becomes dominated by Mo-MF both in mouse and human NSCLC lesions, and TRMF depletion in later stage tumors, had little effect on tumor growth. This study identifies the distinct contribution of the TRMF lineage to early lung cancer invasiveness and establish TRMF as a potential novel target to treat early lung cancer lesions.

2021-04-12 | GSE160711 | GEO

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