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Regulatory T cells converted from T helper 1 cells in tumors suppress cancer immunity via CD39 [scRNA-seq]

ABSTRACT: Although regulatory T (Treg) cells are widely believed to impede anti-tumor immunity, their regulation and functional mechanisms are not well understood. Here, through characterization of multiple cancer models, we identified substantial periphery-induced Treg cells in the tumor microenvironment (TME), depletion of which provoked anti-tumor responses and conferred potent therapeutic effects by increasing functional CD8+ T cells. Through fate-mapping and transfer experiments, we found IFN-γ-expressing T helper (Th) 1 cells developed into Treg cells in tumors, in response to TGF-β signaling. Pseudotime trajectory further revealed the terminal differentiation of Th1-like Treg cells from Th1 cells in the TME. Hence, tumor-resident Treg cells highly expressed T-bet, which was essential for their function in the TME. CD39, highly expressed by T-bet+ Treg cells in both mouse and human tumors, is required for Treg suppression of CD8+ T cell response. In summary, our study has elucidated a developmental pathway of intra-tumoral Treg cells and implicated new ways of targeting them in cancer patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE285225 | GEO | 2024/12/30

REPOSITORIES: GEO

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Regulatory T cells converted from T helper 1 cells in tumors suppress cancer immunity via CD39

Project description:Although regulatory T (Treg) cells are widely believed to impede anti-tumor immunity, their regulation and functional mechanisms are not well understood. Here, through characterization of multiple cancer models, we identified substantial periphery-induced Treg cells in the tumor microenvironment (TME), depletion of which provoked anti-tumor responses and conferred potent therapeutic effects by increasing functional CD8+ T cells. Through fate-mapping and transfer experiments, we found IFN-γ-expressing T helper (Th) 1 cells developed into Treg cells in tumors, in response to TGF-β signaling. Pseudotime trajectory further revealed the terminal differentiation of Th1-like Treg cells from Th1 cells in the TME. Hence, tumor-resident Treg cells highly expressed T-bet, which was essential for their function in the TME. CD39, highly expressed by T-bet+ Treg cells in both mouse and human tumors, is required for Treg suppression of CD8+ T cell response. In summary, our study has elucidated a developmental pathway of intra-tumoral Treg cells and implicated new ways of targeting them in cancer patients.

2024-12-16 | GSE283943 | GEO

Regulatory T cells converted from T helper 1 cells in tumors suppress cancer immunity via CD39

Project description:Although Foxp3-expressing regulatory T (Treg) cells are widely believed to impede anti-tumor immunity, their regulation and functional mechanisms are not well understood. Here, through characterization of multiple cancer models, we identified substantial periphery-induced Treg cells in the tumor microenvironment, depletion of which provoked anti-tumor responses and conferred potent therapeutic effects by increasing CD8+ T cell numbers and cytolytic function. Through fate-mapping and transfer experiments, we found IFN-γ-expressing T helper (Th) 1 cells developed into Treg cells in tumors, in response to TGF-β signaling. Hence, tumor-resident Treg cells highly expressed T-bet, which was essential for their development and function. CD39, highly expressed by T-bet+ Treg cells in both mouse and human tumors, is required for Treg suppression of CD8+ T cell response. In summary, our study has elucidated a developmental pathway of intra-tumoral Treg cells and implicated new ways of targeting them in cancer patients.

2024-02-26 | GSE240961 | GEO

Profiling of lung tumor-infiltrating CD8 T cells according to their expression status of CD39

Project description:Human tumors are infiltrated by various immune cells, including CD8 T cells. CD8 T cells express unique receptors that can recognize peptides at the host’s cells, including tumor cells. After probing the antigen specificity of ex-vivo tumor-infiltrating CD8 T cells from human tumors, we hypothesized that expression of CD39 was correlated with tumor-specificity. The present experiment aims at better characterizing ex-vivo CD39+ vs CD39- CD8 T cells.

2018-05-17 | GSE113588 | GEO

Profiling of colorectal tumor-infiltrating CD8 T cells according to their expression status of CD39

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Blockade of PF4-induced Th1-Treg polarization enhances anti-tumor immunity

Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as regulatory T cells (Tregs) and M2-like tumor associated macrophages (TAMs) that express the enzyme arginase I (Arg1). T helper 1-polarized Treg (Th1-Treg) is a Treg subset that markedly accumulate in tumor tissues, suppressing anti-tumor immunity. However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. Here we show that Arg1-expressing TAMs (Arg1+ TAMs) play critical roles for the high Th1-Treg ratio in TME. Selective depletion of Arg1+ TAMs using the VeDTR system inhibited tumor growth and concurrently reduced the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secreted platelet factor 4 (PF4) that polarized Tregs to Th1-Tregs in a CXCR3-dependent manner. Both genetic PF4 inactivation and PF4 neutralization hindered Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of M2-like TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy by intervening the M2-like TAM/Th1-Treg axis.

2024-11-07 | GSE251735 | GEO

CD39 expression identifies terminally exhausted CD8+ T cells

Project description:Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. CD8+ T cells from subjects with HCV infection were sorted and pelleted and re-suspended in TRIzol (Invitrogen). RNA extraction was performed using the RNAdvance Tissue Isolation kit (Agencourt). Concentrations of total RNA were determined with a Nanodrop spectrophotometer or Ribogreen RNA quantification kits (Molecular Probes/Invitrogen). RNA purity was determined by Bioanalyzer 2100 traces (Agilent Technologies). Total RNA was amplified with the WT-Ovation Pico RNA Amplification system (NuGEN) according to the manufacturer's instructions. After fragmentation and biotinylation, cDNA was hybridized to HG-U133A 2.0 microarrays (Affymetrix).

2015-09-08 | E-GEOD-72752 | biostudies-arrayexpress

Blockade of PF4-induced Th1-Treg polarization enhances anti-tumor immunity (Bulk RNA-Seq)

Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as T helper 1-polarized regulatory T cells (Th1-Tregs). However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. In this work, we demonstrate that selective depletion of arginase I (Arg1)-expressing tumor associated macrophages (Arg1+ TAMs) inhibits tumor growth and concurrently reduces the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secrete platelet factor 4 (PF4) that reinforces interferon-γ (IFN-γ)-induced Treg polarization into Th1-Tregs in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of Arg1+ TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy.

2024-11-07 | GSE252052 | GEO

RNA-Seq of FACS-sorted, KIR-CD39-,KIR+CD39- and KIR+CD39+, Uterine NK cells (uNK cells) from human decidual samples

Project description:Uterine NK cells (uNK cells) form a distinct immune cell population in the endometrium and decidua. Here, we FACS-sorted KIR-CD39-,KIR+CD39- and KIR+CD39+ uNK cells from decidual samples.

2021-02-19 | E-MTAB-8709 | biostudies-arrayexpress

CD39 Identifies Tumor-Reactive CD8 T cells in Patients With Lung Cancer [VDJ]

Project description:We utilized cell surface expression of CD39 to demonstrate that this marker enriches for CD8+ T cells with features of exhaustion, proliferation and tumor reaxtivity.

2022-11-17 | GSE218261 | GEO

CD39 Identifies Tumor-Reactive CD8 T cells in Patients With Lung Cancer [FB]

Project description:We utilized cell surface expression of CD39 to demonstrate that this marker enriches for CD8+ T cells with features of exhaustion, proliferation and tumor reaxtivity.

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