Identification of indoleamine 2, 3-dioxygenase 1 (IDO1) regulated genes in human glioblastoma cell line U87
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE175700 | GEO | 2021/12/10
REPOSITORIES: GEO
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Project description:<p><strong>OBJECTIVES:</strong> High activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.</p><p><strong>MATERIALS AND METHODS:</strong> Systemic IDO1 activity was calculated by Kyn:Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. Dynamic change of IDO1 activity was followed in 24 patients by measuring Kyn:Trp ratio before, during and after RT administration.</p><p><strong>RESULTS:</strong> In 24 patients with dynamic tracking of plasma IDO1 activity, there was no significant alterations observed among the 3 time points (Friedman test, p=0.13). The changing pattern of Kyn:Trp ratio was divided into 4 groups: decreased consistently during RT, first increased then decreased, increased consistently, first decreased then increased. Patients whose Kyn:Trp ratio kept decreasing or first increased then decreased were defined as good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p=0.04; p=0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than bad-change group (p=0.01, HR=0.22). In 113 stage III NSCLC patients with pre-radiation Kyn:Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p=0.079).</p><p><strong>CONCLUSION: </strong>Favorable change of IDO1 activity during RT was associated with superior OS, PFS and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.</p>
2022-08-05 | MTBLS5267 | MetaboLights
Project description:Following therapy, tumour-initiating cells (TICs) survive and give rise to second-line tumours. Gene set enrichment analysis of microarray data and microRNA analysis confirmed the validity of spheroid cultures as models of TICs for breast and prostate cancer and mesothelioma cell lines. Pathway analysis revealed increased Trp metabolism in all types of TICs with indoleamine 2,3-dioxygenase (IDO) as the rate-limiting enzyme. TICs also expressed higher levels of the Trp uptake system consisting of CD98 and LAT1 with functional consequences. Mitocans, represented by vitamin E (VE) analogues, suppressed IDO1 in TICs with functional mitochondrial complex II, a target for the agents. IDO1 expression was regulated via a mechanism involving both transcriptional and post-transcriptional mechanisms. IDO1 increase and its suppression by VE analogues were replicated in TICs from primary human glioblastomas. Our work points to Trp metabolism as a novel mechanism of TICs to bypass the immune surveillance and to VE analogues as agents that remove this ‘mimicry’. Total RNA obtained from from breast cancer (MCF7), mesothelioma (IstMes2) and prostate cancer (LNCaP) adherent cell lines was compared to their corresponding sphere cultures
2013-11-01 | E-GEOD-41980 | biostudies-arrayexpress
Project description:Following therapy, tumour-initiating cells (TICs) survive and give rise to second-line tumours. Gene set enrichment analysis of microarray data and microRNA analysis confirmed the validity of spheroid cultures as models of TICs for breast and prostate cancer and mesothelioma cell lines. Pathway analysis revealed increased Trp metabolism in all types of TICs with indoleamine 2,3-dioxygenase (IDO) as the rate-limiting enzyme. TICs also expressed higher levels of the Trp uptake system consisting of CD98 and LAT1 with functional consequences. Mitocans, represented by vitamin E (VE) analogues, suppressed IDO1 in TICs with functional mitochondrial complex II, a target for the agents. IDO1 expression was regulated via a mechanism involving both transcriptional and post-transcriptional mechanisms. IDO1 increase and its suppression by VE analogues were replicated in TICs from primary human glioblastomas. Our work points to Trp metabolism as a novel mechanism of TICs to bypass the immune surveillance and to VE analogues as agents that remove this ‘mimicry’.
2013-11-01 | GSE41980 | GEO
Project description:Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft post-capillary venules and involves sequential interactions with graft-derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM. We report that unstimulated PCs, like ECs, can directly present alloantigen to TEM but while IFN-γ-activated ECs (γ-ECs) show increased ability to stimulate alloreactive T cells, IFN-γ-activated PCs (γ-PCs) instead suppress TEM proliferation but not cytokine production or signaling. RNA sequencing analysis of PCs, γ-PCs, ECs, and γ-ECs reveal induction of indoleamine 2,3-dioxygenase 1 (IDO1) in γ-PCs to significantly higher levels than in γ-ECs that correlates with tryptophan depletion in vitro. Consistently, shRNA knockdown of IDO1 markedly reduces -PC-mediated immunoregulatory effects. Adoptively transferred T cells induced PC expression of IDO1 in allogeneic human skin grafts on immunodeficient mice. We conclude that immunosuppressive properties of human PCs are not intrinsic but instead result from IFN-γ-induced IDO1-mediated tryptophan depletion.
2018-05-09 | GSE109322 | GEO
Project description:Indoleamine 2, 3-dioxygenase 1 (IDO1) is a metabolic enzyme catalyzing the conversion of the essential amino acid tryptophan to kynurenine. It is induced by IFNg and its expression is linked to poor prognosis across various cancer types. T cells are particularly sensitive to IDO1-dependent tryptophan deprivation in the tumor microenvironment, leading to tumor immune resistance. Therefore, IDO1 inhibitors, such as epacadostat, have been developed, aiming to restore T cell antitumor activity. However, a recent phase III trial assessing the clinical benefit of epacadostat with the PD-1 antibody pembrolizumab in melanoma failed. This prompted us to study the role of IDO1, and the effect of its inhibition, on tumor cells that are under IFNg treatment and T cell attack. We showed that IDO1-mediated tryptophan depletion contributes to the anti-tumor effect of CD8 T cells. Thus, while epacadostat expectedly replenished tryptophan -the desired effect-, this led to adverse protection of melanoma cells from T cell-derived IFNg. RNA sequencing and ribosome profiling of (patient-derived) melanoma cell lines revealed that IFNg caused general protein translation shut down, which was reversed by IDO1 inhibition. Impaired translation was accompanied by an amino acid deprivation-dependent stress response driving ATF4high and MITFlow transcriptomic signatures, which was also observed in melanoma patient tumors. Downregulation of MITF in tumors and PDX- derived cell lines upon treatment was strongly predictive of response to response, to checkpoint blockade-treatment and IFNg, respectively. Conversely, MITF restoration in cultured tumor cells caused T cell resistance. These results highlight the critical role of tryptophan in the melanoma response to T cell-derived IFNg, uncovering an unexpected negative consequence of IDO1 inhibition.
2023-01-16 | GSE198460 | GEO
Project description:Identification of indoleamine 2, 3-dioxygenase 1 (IDO1) regulated genes in human glioblastoma cell line U87
| PRJNA733217 | ENA
Project description:CD40-stimulating immunotherapy elicits potent anti-tumor responses, which are mainly T-cell dependent. Here, we have investigated how tumor endothelial cells respond to CD40-stimulating immunotherapy by isolating endothelial cells from B16.F10 melanoma in anti-CD40 treated or isotype treated mice followed by RNA-sequencing. Gene set enrichment analysis revealed an increase in interferon- related responses in tumor endothelial cells following anti-CD40 therapy. The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) was preferentially expressed in endothelial cells, and it was up-regulated upon anti-CD40 treatment. IDO1 expression in tumor endothelium was positively correlated to T-cell infiltration and to increased expression of IFNγ in the tumor microenvironment. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Combining agonistic anti-CD40 therapy with the IDO1 inhibitor epacadostat delayed tumor growth and increased survival in B16.F10 tumor-bearing mice, which was associated with increased activation of tumor-infiltrating T-cells. Hereby, we have uncovered an immunosuppressive feedback mechanism, in which tumor vessels limit the efficacy of cancer immunotherapy by up-regulating IDO1 in response to T-cell activation.
2020-04-06 | GSE130679 | GEO
Project description:Neutrophil granulocytes are the major cells involved in the Chlamydia trachomatis (C.trachomatis)-mediated inflammation and histopathology. A key gene in human intracellular antichlamydial defense is the tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO), which limits the growth of the tryptophan auxotroph Chlamydia. Despite its importance, the role of IDO in the intracellular defense against Chlamydia in neutrophils has not yet been characterized. Affymetrix microarrays were used to obtain global gene expression data for monitoring the effect of C. trachomatis serovar D infection on the transcriptome of human neutrophil granulocytes.
2021-11-08 | GSE180238 | GEO
Project description:Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. Hitherto, indoleamine-2,3-dioxygenase 1 (IDO1) or tryptophan- 2, 3-dioxygenase (TDO2) are recognized as the main Trp-catabolizing enzymes (TCEs) responsible for the generation of AHR agonists. Here, the ability of the aromatic L-amino acid oxidase, interleukin 4 induced 1 (IL4I1), to activate the AHR was investigated using IL4I1 knockout CAS-1 glioblastoma cells.
2020-08-19 | GSE149910 | GEO
Project description:Tumor infiltrating lymphocytes (TILs) play a critical role in modulating the immunoediting features in certain malignancies like triple negative breast cancer (TNBC). Nevertheless, much is still unknown concerning the specific responses of tumors when challenged by lymphocyte infiltration. Based on this void, we conducted a immuno-phenotype comparison using mRNA sequencing between the TNBC cell line MDA-MB-231 and the luminal breast cancer cell line MCF7 after both were co-cultured with activated human T-cells. We found that, though the cytokine-induced immune signature of the two cell lines was similar, MDA-MD-231 cells were able to transcribe IDO1 at a significantly higher level than MCF7 cells. Though no differences occurred in upstream JAK/STAT1 signaling or IDO1 mRNA stability between the two cell lines, stimulation with IFNγ was able to differentially induce IDO protein expression and enzymatic activity in ER- cell lines compared to ER+ cell lines. Further experiments show that 5-aza-deoxycytidine treatment was able to reverse suppression of IDO1 expression in MCF7 cells, suggesting DNA methylation as a potential determinant in IDO1 induction. By analyzing TCGA breast cancer datasets, we discovered subtype-specific mRNA and promoter methylation differences in IDO1, with TNBC/basal subtypes exhibiting lower methylation/higher expression and ER+/luminal subtypes exhibiting higher methylation/lower expression. We confirmed this trend of IDO1 methylation by bisulfite pyrosequencing breast cancer cell lines and an independent cohort of primary breast tumors. Taken together, these findings suggest that IDO1 methylation regulates anti-immune responses in breast cancer subtypes and could be used as a predictive biomarker for IDO inhibitor-based immunotherapy. To determine the immunomodulatory effects of cytokines secreted by activated human T-cells on breast cancer cells, we performed RNAseq analysis in MCF7 and MDA-MB-231 cells, after co-culturing them with normal PBMCs activated with anti-CD3/CD28 antibodies in a contact-independent manner. MDA-MB-231 or MCF7 cells were co-cultured with PBMCs alone or the conditioned-media or a combination of both for 24 hrs, and then total RNA was harvest for RNA-seq analysis.
2016-06-01 | E-GEOD-73527 | biostudies-arrayexpress