Targeting the CBM signalosome induces Treg to prime the tumor environment for effective immune checkpoint therapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129480 | GEO | 2019/04/09
REPOSITORIES: GEO
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Project description:Targeting the CBM signalosome induces Treg to prime the tumor environment for effective immune checkpoint therapy
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Project description:Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. Here we report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg), and controls cell fate determination. TH17 but not Treg-inducing conditions resulted in strong upregulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited TH17 development while promoting Treg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1a (HIF1a) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1a-dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells. Lack of HIF1a resulted in diminished TH17 development but enhanced Treg differentiation, and protected mice from autoimmune CNS inflammation. Our studies demonstrate that HIF1a-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. Naïve CD4 T cells from wild-type and HIF1a-deficient mice (in triplicates each group) were differentiated under TH17 conditions for 2.5 days, and RNA was analyzed by microarrays.
2011-06-07 | E-GEOD-29765 | biostudies-arrayexpress
Project description:Naïve Treg cells were purified from the resting spleens of FoxP3-GFP knock-in mice made in the 129/SvJ strain. Ascites Treg cells were tumor-associated FoxP3-GFP+ cells sorted from the tumor ascites of 129/SvJ mice IP-injected with 1 x 10e6 RMAS cells 5 days earlier; Spleen-T Treg cells were purified from the spleens of the same tumor-bearing mice. Keywords: in vivo samples Affymetrix MOE430v2 arrays were used to perform gene expression studies. The purity of the sorted Treg cells is >99%.
2008-10-31 | E-GEOD-13409 | biostudies-arrayexpress
Project description:Regulatory T (Treg) cells play an important role in the induction and maintenance of peripheral tolerance. Treg cells also suppress a variety of other immune responses, including anti-tumor and alloimmune responses. We have previously reported that tumor-activated Treg cells express granzyme B and that granzyme B is important for Treg cell-mediated suppression of anti-tumor immune responses (GSE13409). Here, we report that allogeneic mismatch also induces the expression of granzyme B. Granzyme B-deficient mice challenged with fully mismatched allogeneic P815 mastocytoma cells have markedly improved survival compared to WT and other granzyme- or perforin-deficient mice, suggesting an immunoregulatory role for granzyme B in this setting. Treg cells harvested from the tumor environment of P815-challenged mice express granzyme B. Treg cells also express granzyme B in vitro during mixed lymphocyte reactions and in vivo in a mouse model of graft-versus-host disease (GVHD). However, in contrast to findings from our previously published tumor model, granzyme B is not required for the suppression of effector T cell (Teff) proliferation in in vitro Treg suppression assays stimulated by either Concanavalin A or allogeneic antigen presenting cells. Additionally, in an ex vivo assay, sort-purified in vivo-activated CD4+Foxp3+ Treg cells from mice with active GVHD -- under conditions known to induce granzyme B expression in Treg cells -- suppressed Teff cell proliferation in a granzyme B-independent manner. Adoptive transfer of naive granzyme B-deficient CD4+CD25+ Treg cells into a mouse model of GVHD rescued hosts from lethatlity equivalently to naive wild-type Treg cells. Serum analysis of GVHD-associated cytokine production in these recipients also demonstrated that Treg cells suppressed production of IL-2, IL-4, IL-5, GM-CSF, and IFN-gamma in a granzyme B-independent manner. In order to determine whether the context in which Treg cells are activated alters the intrinsic properties of Treg cells, we used Foxp3 reporter mice to obtain gene expression profiles of CD4+Foxp3+ Treg cells purifed from naive resting spleens, spleens from mice with acute GVHD, and from ascites fluid of mice challenged intraperitoneally with allogeneic P815 tumor cells. Unsupervised analyses revealed distinct activation signatures of Treg cells among the 3 experimental groups. Taken together, these findings demonstrate that granzyme B is not required for Treg cell-mediated suppression of GVHD, which is in contrast to what we have previously reported for Treg cell function in the setting of tumor challenge. Cell intrinsic differences could partially account for these differential phenotypes. These data also suggest the therapeutic potential of targeting specific Treg cell suppressive functions in order to segregate GVHD and graft-versus-tumor effector functions. Experiment Overall Design: Six replicates of Naive CD4+Foxp3+ Treg cells were purified from resting spleens, five replicates of allogeneic tumor-activated Treg cells and three samples of GVHD-activated Treg cells. Experiment Overall Design: Naive reps 1-3 are controls for the GVHD-activated samples. Experiment Overall Design: Naive reps 4-6 are controls for the Allogeneic tumor-activated samples.
2009-09-15 | E-GEOD-16210 | biostudies-arrayexpress
Project description:Purpose: Identification of the differentially expressed genes and metabolic pathways in resting and activated WT and BATF-deficient Treg cells Methods: RNA was purified from resting of stimulated (aCD3-CD38/IL-2 for 48 h)Treg cells isolated from WT or Foxp3CreBatffl/fl mice Results: Loss of BATF promotes triacylglycerol biosynthesis in Treg cells. Conclusions: BATF is crucial to coordinate the suppressive function and triacylglycerol metabolism of Treg cells.
2021-03-02 | GSE149197 | GEO
Project description:Naïve Treg cells were purified from the resting spleens of FoxP3-GFP knock-in mice made in the 129/SvJ strain. Ascites Treg cells were tumor-associated FoxP3-GFP+ cells sorted from the tumor ascites of 129/SvJ mice IP-injected with 1 x 10e6 RMAS cells 5 days earlier; Spleen-T Treg cells were purified from the spleens of the same tumor-bearing mice. Keywords: in vivo samples
2008-10-31 | GSE13409 | GEO
Project description:Purpose: Identification of Gpx4-dependent genes in resting and activated Treg cells Methods: RNA was purified from resting of stimulated (aCD3-CD38 for 4 h) splenic Treg cells sorted from WT or Foxp3CreGpx4fl/fl mice Conclusions: Gpx4 prevents lipid peroxidation and ferroptosis of activated Treg cells..
2021-10-31 | GSE160338 | GEO
Project description:Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. Here we report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg), and controls cell fate determination. TH17 but not Treg-inducing conditions resulted in strong upregulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited TH17 development while promoting Treg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1a (HIF1a) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1a-dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells. Lack of HIF1a resulted in diminished TH17 development but enhanced Treg differentiation, and protected mice from autoimmune CNS inflammation. Our studies demonstrate that HIF1a-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.
2011-06-07 | GSE29765 | GEO
Project description:To investigate the underlying mechanisms of Treg cell dysfunction in the mtDNANZB mice during activation, we compared the gene expression profiles of resting and activated Treg cells from mtDNAB6 and mtDNANZB mice.
2024-12-08 | GSE280896 | GEO
Project description:Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti‐tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi‐omic single‐cell analysis, we show that Flt3L therapy increases all cDC subsets in orthotopic E0771 triple‐negative breast cancer, but this did not result in a reduction of tumor growth. Interestingly, a CD81+migcDC1 population, likely developing from cDC1, was induced upon Flt3L treatment. This subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a higher Treg‐inducing potential compared to other migcDCs. To shift the cDC phenotype towards a T‐cell stimulatory phenotype, CD40 agonist therapy was administered in combination with Flt3L. However, while αCD40 reduced tumor growth, Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg promoting CD81+migcDC1. Nonetheless, while Treg‐depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti‐tumor responses and therefore might not be beneficial for the treatment of triple‐negative breast cancer, though could still be of use to increase cDC numbers for autologous DC‐therapy.
2023-07-26 | GSE225539 | GEO