HDACi-dependent microenvironmental normalization overcomes tumor burden-induced T-cell exhaustion [Affymetrix]
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ABSTRACT:
PROVIDER: PRJNA998395 | ENA |
REPOSITORIES: ENA
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Project description:HDACi-dependent microenvironmental normalization overcomes tumor burden-induced T-cell exhaustion
| PRJNA998399 | ENA
Project description:HDACi-dependent microenvironmental normalization overcomes tumor burden-induced T-cell exhaustion [RNA-seq]
| PRJNA998403 | ENA
Project description:Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. While immune checkpoint blockade and adoptive T cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden-related pathway changes that are conducive to T-cell exhaustion. We then determined if microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. Experimental Design: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor (HDACi) MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. Results: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively up-regulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2-STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed towards terminal effector cell-like CD44+ Tim-3hi TCF1- CD127- KLRG1+ differentiation. Conclusion: Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation. We used whole transcriptome arrays (Clariom D) to determine the effect of MS-275 on exhausted T cells in ACT+/-MS-275-treated mice
2023-07-29 | GSE238222 | GEO
Project description:Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. While immune checkpoint blockade and adoptive T cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden-related pathway changes that are conducive to T-cell exhaustion. We then determined if microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. Experimental Design: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor (HDACi) MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. Results: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively up-regulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2-STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed towards terminal effector cell-like CD44+ Tim-3hi TCF1- CD127- KLRG1+ differentiation. Conclusion: Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation.
2023-07-29 | GSE238233 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-07-29 | GSE238234 | GEO
Project description:Alkylating Agent-Induced ER Stress Overcomes Microenvironmental Resistance to Lymphoma Therapy
| PRJNA528647 | ENA
Project description:Transcriptional profiling of cultured CD1 mouse embryonic kidneys (E13.5) comparing HDACi-treated kidneys with control drug-treated kidneys. Studies in our lab showed that pharmacological inhibition of HDAC activity in ex-vivo cultured metanephroi results in extensive defects in kidney development, including impaired UB branching, tubulogenesis, and glomerulogenesis, accompanied by cell cycle arrest and apoptosis.The goal of the microarray analysis was to elucidate the morphogenetic pathways affected by HDACi. Two-condition experiment, HDACi-treated E13.5 kidneys (Scriptaid 2.0 μg/ml x 6hrs) vs. Control drug-treated E13.5 kidneys (Nullscript 2.0 μg/ml x 6hrs). Biological replicates: 3 control replicates, 3 HDACi-treated replicates. Two-color Agilent 4x44k chips with dye-swap on 2 of 4 arrays.
2010-08-01 | E-GEOD-19581 | biostudies-arrayexpress
Project description:Transcriptomic signatures, or biomarkers, of toxicity can facilitate rapid mechanistic analysis of chemicals using high-content transcriptomic data and identification of potential hazards to human health. We developed an 81-gene transcriptomic biomarker, named TGx-HDACi, to detect histone deacetylase inhibitors (HDACi) in TK6 human lymphoblastoid cells after 4 hours of chemical exposure. This work leveraged an established transcriptomic biomarker of DNA damage, TGx-DDI, which was developed by Heng Hong Li et al. (2015); TGx-DDI contains 63 genes and can distinguish between DNA damage-inducing (DDI) and non-DDI agents after 4 hours of exposure in TK6 cells. TGx-HDACi was derived from Templated Oligo-Sequencing (TempO-Seq) whole transcriptome gene expression profiles of 20 reference compounds, consisting of 10 HDACi and 10 non-HDACi compounds. Fourteen of the TGx-HDACi reference compounds are also part of the 28-compound reference set for TGx-DDI. The nearest shrunken centroid (NSC) method was applied to the gene expression profiles and 81 genes were identified that accurately identified HDACi compounds in the NSC probability analysis. The classification performance of TGx-HDACi was validated using an additional set of 11 test compounds (4 HDACi and 7 non-HDACi). Thus far, TGx-HDACi has demonstrated 100% accuracy. The availability of TGx-HDACi increases the diversity of tools that can facilitate mode of action analysis of toxicants using gene expression profiling.
2021-04-14 | GSE164478 | GEO
Project description:Epigenetic modifying enzymes are commonly mutated in diffuse large B cell lymphoma (DLBCL). Importantly, genetics abnormalities lead to inactivation of HAT, which tilt the balance in favor of decreased protein acetylation in DLBCL cells. This suggests that protein acetylation regulation is an important factor in DLBCL pathogenesis and a potential target for therapy. We developed resistant cell lines to the histone deacetylase inhibitor (HDACi) vorinostat, in order to better define molecular mechanisms of action of HDACi in lymphoma cells. We found that cells resistant to HDACi have increased protein synthesis and proteasomal degradation. Additionally, cells resistant to HDACi have acquired increased susceptibility to proteasome inhibitors and this correlates with activation of the unfolded protein response. Importantly, using transcriptional signatures found in our resistant lymphoma cell line model, we show that tumors from DLBCL patients treated but unresponsive to HDACi therapy undergo similar changes. Together, these data show, for the first time, that HDACi may be used to prime DLBCL for targeted therapy including proteasome inhibitors. Gene expression in U937 cells after 12h exposure to 2µM vorinostat and after development of resistance to 2 µM vorinostat, with and without vorinostat in the media.
2016-06-01 | E-GEOD-58421 | biostudies-arrayexpress
Project description:We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible towards treatment with class I histone deacetylase inhibitors (HDACi). However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy. Gene expression changes in HDACi entinostat-treated cells identified, the cell cycle protein PLK1 as a potential second target. Indeed, MYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1 inhibitors as monotherapy. Moreover, entinostat and PLK1i in combination act synergistically in MYC-driven MB, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect of both drugs as monotherapy and in combination is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with combination. However, further screening of blood-brain barrier penetrating PLK1is is necessary to determine the true potential of the combination. We use microarry to interrogate the expression differences in vehicle, entinostat, volasertib or combination treated cells.
2023-05-15 | GSE220748 | GEO