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Opposing functions of distinct regulatory T cell subsets in colorectal cancer

ABSTRACT: Regulatory T (Treg) cells are considered major contributors to the growth of solid organ tumors, with the notable exception of colorectal cancer (CRC), despite the documented abundance of Treg cells in CRC. Here, we demonstrate that IL-10⁺ and IL-10⁻ Treg cells constitute two distinct subsets with opposing functions: IL-10⁺ Treg cells counteract, while IL-10⁻ Treg cells promote, the growth of genetically engineered CRC tumors. Our findings suggest that the tumor-suppressive function of IL-10⁺ Treg cells is mediated by their suppression of effector CD4⁺ T cell production of IL-17, a cytokine that directly stimulates CRC tumor cell proliferation. Consistently, IL-10⁺ Treg cells were more abundant in both mouse and human CRC tumors than in tumor-adjacent normal colon tissue, whereas IL-10⁻ Treg cells exhibited the opposite distribution. Furthermore, gene expression signatures associated with IL-10⁺ and IL-10⁻ Treg cells correlated with better and worse disease prognoses in human CRC, respectively. This functional dichotomy between Treg subsets provides a rationale for therapeutic strategies aimed at selectively targeting pro-tumoral Treg cells while preserving their anti-tumoral counterparts across various barrier tissue cancers that harbor both subsets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290616 | GEO | 2025/12/15

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE290616_aggr.csv.gz	Csv
	GSE290616_atac_fragments.tsv.gz	Tabular
	GSE290616_filtered_feature_bc_matrix.h5	Other
	GSE290616_metadata.tsv.gz	Tabular

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Similar Datasets

Opposing functions of distinct regulatory T cell subsets in colorectal cancer

Project description:Regulatory T (Treg) cells are considered major contributors to the growth of solid organ tumors, with the notable exception of colorectal cancer (CRC), despite the documented abundance of Treg cells in CRC. Here, we demonstrate that IL-10⁺ and IL-10⁻ Treg cells constitute two distinct subsets with opposing functions: IL-10⁺ Treg cells counteract, while IL-10⁻ Treg cells promote, the growth of genetically engineered CRC tumors. Our findings suggest that the tumor-suppressive function of IL-10⁺ Treg cells is mediated by their suppression of effector CD4⁺ T cell production of IL-17, a cytokine that directly stimulates CRC tumor cell proliferation. Consistently, IL-10⁺ Treg cells were more abundant in both mouse and human CRC tumors than in tumor-adjacent normal colon tissue, whereas IL-10⁻ Treg cells exhibited the opposite distribution. Furthermore, gene expression signatures associated with IL-10⁺ and IL-10⁻ Treg cells correlated with better and worse disease prognoses in human CRC, respectively. This functional dichotomy between Treg subsets provides a rationale for therapeutic strategies aimed at selectively targeting pro-tumoral Treg cells while preserving their anti-tumoral counterparts across various barrier tissue cancers that harbor both subsets.

2025-12-15 | GSE290619 | GEO

Opposing functions of distinct regulatory T cell subsets in colorectal cancer

2025-12-15 | GSE290622 | GEO

Opposing functions of distinct regulatory T cell subsets in colorectal cancer

2025-12-15 | GSE290618 | GEO

Opposing functions of distinct regulatory T cell subsets in colorectal cancer

2025-12-15 | GSE290617 | GEO

Opposing functions of distinct regulatory T cell subsets in colorectal cancer

2025-12-15 | GSE311260 | GEO

Whole genome expression analysis of tumor regulatory T cells expressing interleukin-10

Project description:The tumor microenvironment contains high frequencies of inflammatory regulatory T (Treg) cells. These Treg exhibit superior regulatory function compared with those from other environments such as the spleen, partially due to expression of anti-inflammatory interleukin-10. In order to gain insight into the origins and functional roles of different Treg subsets, we used whole genome microarray analysis to characterize tumor IL-10+ and tumor IL-10- Treg subsets obtained from VERT-X reporter mice bearing transplantable tumors, along with total tumor Treg and spleen Treg from FoxP3-EGFP reporter mice. Few genes were found to differ between IL-10+ and IL-10- tumor Treg subsets (29 upregulated, 88 downregulated), suggesting a common origin of each Treg subset. The specific gene expression profile of IL-10+ tumor Treg was associated with the tumor microenvironment and absent from spleen Treg, suggesting it to be driven by components of the inflammatory tumor microenvironment. The IL-10+ tumor Treg gene expression profile displayed upregulation of genes associated with a higher activation state and greater effector function. Pooled MC38 tumor tissue from VERT-X or FoxP3-EGFP reporter mice were used to obtain IL10+ tumor Treg (VERT-X), IL10- tumor Treg (VERT-X) and total tumor Treg (FoxP3-EGFP). Spleens from tumor-free FoxP3-EGFP mice were used for spleen Treg. Three experiments for each population gave a total 12 RNA samples.

2013-08-31 | E-GEOD-49380 | biostudies-arrayexpress

Whole genome expression analysis of tumor regulatory T cells expressing interleukin-10

2013-08-31 | GSE49380 | GEO

Interleukin-23 receptor signaling in regulatory T cells in a mouse model of inflammation-associated cancer.

Project description:The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal carcinogenesis (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC. In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane/dextran sodium sulphate in wild-type Treg cell reporter mice (WT, Foxp3YFP-Cre), and mice harboring a Treg cell-specific deletion of IL-23 (Il23rΔTreg). Il23rΔTreg mice had increased dysplasia compared to WT mice associated with decreased tumor-infiltrating macrophages. The role of Treg cell IL-23R in sporadic CRC was examined via orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon/rectum of mice. In the sporadic cancer model, Il23rΔTreg mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of Il23rΔTreg mice had a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4+ T cells. This data suggests that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4+ T cells that in turn promotes pro-inflammatory macrophages to clear tumors. These findings further support and highlight the importance of selecting a physiologically relevant model based on the type of cancer in which to evaluate the role of specific genes in late tumorigenesis. Finally, single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that IL23R was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells.

2024-02-28 | GSE240707 | GEO

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

Regulatory T cells Maintain Lung Function Upon Infectious Damage

Project description:RNA-Seq analysis of Treg cell subsets isolated from lungs of Il10GFPFoxp3Thy1.1 mice. Thy1.1+ Treg cells were FACS-sorted into IL-10–IL-18R–, IL-10+IL-18R– and IL10–IL-18R+ populations on day 5 following intranasal infection with 0.5 LD50 PR8-OTI influenza virus. mRNA profiles of each Thy1.1+ Treg cell population (IL-10–IL-18R–, IL-10+IL-18R– and IL10–IL-18R+) from lungs on day 5 following influenza infection from 5 infected mice, sorted into TRIzol LS reagent.

2015-08-27 | E-GEOD-71588 | biostudies-arrayexpress

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