Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion

ABSTRACT: Abstract: Regulatory T cells (Tregs) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Tregs subvert beneficial anti-tumor immunity by modulating inhibitory receptor (IR) expression on tumor infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms remain elusive. Here we show that interleukin-10 (IL10) and interleukin-35 (IL35; a heterodimer of Ebi3 and IL12) are reciprocally expressed by Treg-subpopulations in the tumor microenvironment (TME) and cooperatively promote intratumoral T cell exhaustion. Treg-restricted deletion of either Il10/Ebi3 or dual deletion resulted in delayed tumor growth and significant reduction of transcriptomic exhaustion signature associated with reduced expression of B lymphocyte-induced maturation protein-1 (BLIMP1; Prdm1). While the two cytokines share the BLIMP1 axis to drive multi-IR expression; they differentially impact effector vs. memory fate, highlighting their overlapping and non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated adaptive plasticity in inhibitory cytokine expression pattern by Tregs in TME for maximal immunosuppression. Data purpose: to understand the segregated cytokine expression pattern and the preferential generation of single cytokine positive Treg subpopulations, we performed single cell RNASeq (scRNAseq) contrasting Tregs isolated from naïve, unchallenged LNs or day 14 B16 tumor from Foxp3Cre-YFP WT mice

ORGANISM(S): Mus musculus

PROVIDER: GSE126184 | GEO | 2019/04/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Adaptive plasticity of IL10 + and IL35 + regulatory T cells

Project description:Regulatory T cells (T regs) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. T regs subvert beneficial anti-tumor immunity by modulating inhibitory receptor (IR) expression on tumor infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms remain elusive. Here we show that interleukin-10 (IL10) and interleukin-35 (IL35; Ebi3/IL12α heterodimer) are divergently expressed by T reg subpopulations in the tumor microenvironment (TME) and cooperatively promote intratumoral T cell exhaustion. T reg -restricted deletion of Il10 and/or Ebi3 resulted in delayed tumor growth, loss of multi-IR expression, and reduced intratumoral CD8 + T cell exhaustion signature. While Il10 or Ebi3 loss was associated with reduced expression of B lymphocyte-induced maturation protein-1 (BLIMP1; Prdm1), IL10 and IL35 differentially impacted effector versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for IL10 and IL35, produced by limits effective anti-tumor immunity

2019-04-02 | GSE127735 | GEO

RNA-seq analysis of transcriptomes of IL35-Treg cells and the Blimp1-Treg cells

Project description:To gain in depth transcriptional information about the two subsets of effector Tregs, we performed RNA-seq analysis to compare the transcriptomes of Thy1.1+Blimp1- (Ebi3-Tregs) and Thy1.1-Blimp1+ (Blimp1-Tregs) Tregs. We found ~173 unique genes with differential expression between the two effector subsets.

2019-08-31 | GSE103456 | GEO

Potent anti-tumor immunity and reversal of CD8 T cell exhaustion by spatially and functionally targeting Treg cells in the tumor microenvironment

Project description:Regulatory T cells (Tregs) are a key mediator of resistance to cancer immunotherapy, including anti-PD-(L)1 immune checkpoint blockade (ICB). Tregs perpetually infiltrate tumors and hamper effective anti-tumor immunity. The mechanisms driving Treg infiltration into the tumor microenvironment (TME) and the consequence on CD8+ T cell exhaustion remains elusive. Herein, we report that heat shock protein gp96 (GRP94) is indispensable for Treg infiltration into the tumor, primarily through gp96’s roles in chaperoning integrins. Among various gp96-dependent integrins, we found that only LFA-1 (αL integrin) but not integrin αV, CD103 (αE) or β7 was required for Treg homing into the tumors. Loss of Treg infiltration into the TME by genetically deleting gp96/LFA-1 potently induces rejection of multiple ICB-resistant murine cancer models in a CD8+ T cell dependent manner without loss of self-tolerance. Moreover, gp96 deletion impeded Treg activation primarily by suppressing IL-2/phosphorylated STAT5 (pSTAT5) signaling pathway, which also contributes to tumor regression. Notably, by a mechanism in part through competing for IL-2 in the TME, intra-tumoral Tregs prevent activation of CD8+ tumor-infiltrating lymphocytes (TILs), drive TOX induction and induce bona fide CD8+ T cell exhaustion. By contrast, Treg ablation leads to a striking CD8+ T cell activation without TOX induction, demonstrating clear uncoupling of the two processes. Our study reveals that the gp96/LFA-1 axis plays a fundamental role in Treg biology and intratumoral CD8+ T cell exhaustion. We suggest that, Treg-specific targeting of gp96/LFA-1 represents a novel strategy for cancer immunotherapy without inflicting autoinflammatory conditions.

2024-05-05 | GSE266362 | GEO

Interleukin-35-mediated induction of a novel regulatory T cell population

Project description:Regulatory T cells (Tregs) play a critical role in the maintenance of immunological self-tolerance. Naïve human or murine T cell treatment with the inhibitory cytokine IL35 induces a regulatory population, termed iTR35, that mediates suppression via IL35, but not IL10 or TGFβ, neither express nor require Foxp3, are strongly suppressive in five in vivo models, and exhibit in vivo stability. Treg-mediated suppression induces iTR35 generation in an IL35- and IL10-dependent manner in vitro, and in inflammatory conditions in vivo in Trichuris-infected intestines and within the tumor microenvironment, where they appear to contribute to the regulatory milieu. iTR35 may constitute a key mediator of infectious tolerance and may contribute to Treg-mediated tumor progression, and ex vivo-generated iTR35 may possess therapeutic utility. Five IL35-treated samples, in parallel with 5 control-treated samples, were compared to 3 Treg and 3 Tconv cell samples.

2010-09-18 | E-GEOD-24210 | biostudies-arrayexpress

IL-35-mediated induction of a potent regulatory T cell population.

2010-09-18 | GSE24210 | GEO

Tumor-Infiltrating Regulatory T Cell Accumulation in the Tumor Microenvironment is Mediated by IL33/ST2 Signaling

Project description:Regulatory T cells (Tregs) are enriched in the tumor microenvironment (TME) and suppress anti-tumor immunity. However, the origin of tumor-infiltrating (TI) Tregs and the molecular mechanism underlying their TME accumulation are poorly understood. Although IL-33 was reported to regulate the expansion and function of Tregs, its direct role on TI Tregs and its contribution to tumor progression remain uncertain. Firstly, we demonstrated TI Tregs were primarily thymus-derived. More importantly, we found using comparative transcriptome analysis that proliferation-related genes were prominently upregulated in TI Tregs compared with TI CD4+Foxp3− conventional T cells or splenic Tregs of same tumor-bearing mice. One of these genes, ST2, an interleukin-33 (IL-33) receptor, was identified as a potential factor driving Treg accumulation in the TME. Indeed, IL-33-directed ST2 signaling induced the preferential proliferation of TI Tregs and enhanced tumor progression, while genetic deletion of ST2 in Tregs limited their TME accumulation and delayed tumor growth. These data demonstrate the IL-33/ST2 axis in Tregs as one of the critical pathways for the preferential accumulation of thymus-derived Tregs in the TME and suggest the axis as a potential therapeutic target for cancer immunotherapy.

2020-08-12 | GSE152022 | GEO

Inhibition of PARP11 inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies.

Project description:Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenviroment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here we demonstrate that Poly-(ADP-ribose)-polymerase-11 (PARP11) acts as an essential regulator of TI-Tregs regulatory and protumorigenic activities. Expression of PARP11 correlated with TI-Treg infiltration and poor responses to immune checkpoint blockade (ICB) in human cancer patients. PARP11 was induced in the TI-Treg cells by tumor-derived factors including adenosine and prostaglandin E2. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivated TI-Treg cells and reinvigorated anti-tumor immune responses. Accordingly, ITK7 decelerated tumor growth and significantly increased the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of CAR T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

2023-12-07 | GSE249299 | GEO

YTHDF2/m6A/NF-κB axis controls anti-tumor immunity by regulating intratumoral Tregs

Project description:N6-methyladenosine (m6A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of the m6A reader YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that the loss of YTHDF2 in regulatory T (Treg) cells reduces tumor growth in mice. Deletion of Ythdf2 in Tregs does not affect peripheral immune homeostasis but leads to increased apoptosis and impaired suppressive function of Treg cells in the TME. Elevated tumor necrosis factor (TNF) signaling in the TME promotes YTHDF2 expression, which in turn regulates NF-κB signaling by accelerating the degradation of m6 A-modified transcripts that encode NF-κB-negative regulators. This TME-specific regulation of Treg by YTHDF2 points to YTHDF2 as a potential target for anti-cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance anti-tumor immune response while avoiding Treg cells in the periphery to minimize undesired inflammations.

2023-06-06 | GSE216960 | GEO

High-dimensional single cell analysis of T cells infiltrating human intrahepatic cholangiocarcinoma [RNA-Seq]

Project description:In tumors, CD4+ T regulatory cells (Tregs), a specialized subtype of cells indispensable for maintaining immune homeostasis and tolerance, inhibit anti-tumor immunity and response to immunotherapy. Selective targeting of the hyperactive Tregs promote tumor regression and synergizes with checkpoint blockade without severe, systemic autoimmunity, that is otherwise observed with non-specific Treg depletion. However, is poorly defined how Treg hyper-activation regulated in the tumor microenvironment. We found that mesenchyme homeobox-1 (MEOX1) a transcription factor with an important role in skeleton formation during development, is specifically overexpressed by intrahepatic cholangiocarcinoma infiltrating Treg compared to Treg cells present in the peritumoral tissue. Integration of transcriptomic data revealed that MEOX1 positively regulates several molecules involved in immunosuppression, including CTLA-4, ICOS and IL10, as well as a tumor Treg-specific signature associated with disease progression. Thus, interfering with the MEOX1-dependent molecular program may represent a novel immunotherapeutic approach capable to block immunosuppression in the tumor microenvironment without inducing autoimmunity in peripheral tissues.

2022-06-30 | GSE171895 | GEO

High-dimensional single cell analysis of T cells infiltrating human intrahepatic cholangiocarcinoma [scRNA-Seq]

2022-06-30 | GSE171899 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data