Single cell RNA-sequencing shows generation of highly proliferative and robust effector CD8 T cell populations in the tumor.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE140522 | GEO | 2025/11/01
REPOSITORIES: GEO
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Project description:To determine how Entinostat (ENT) treatment affected tumor-infiltrating CD8 T cells, we treated TS/A tumor-bearing mice with vehicle or ENT daily beginning at day 7 and performed RNAseq on CD8 T cells isolated from tumors on day 10 and day 17. These data show that ENT progressively altered both the function and distribution of infiltrating CD8 T cells.
2025-11-01 | GSE140285 | GEO
Project description:Single cell RNA-sequencing shows generation of highly proliferative and robust effector CD8 T cell populations in the tumor.
| PRJNA590125 | ENA
Project description:Immune checkpoint inhibition (ICI) has revolutionized treatment in cancers that are naturally immunogenic by enabling infiltration of T cells into the tumor microenvironment (TME) and promoting cytotoxic signaling pathways. Tumors possessing complex immunosuppressive TME’s such as breast and pancreatic cancers present unique therapeutic obstacles as response rates to ICI remain low. Such tumors often recruit myeloid-derived suppressor cells (MDSCs) whose functioning prohibits both T-cell activation and infiltration. We attempted to sensitize these tumors to ICI using epigenetic modulation to target MDSC trafficking and function to foster a less immunosuppressive TME. We showed that combining a histone deacetylase inhibitor, entinostat (ENT), with anti–PD-1, anti–CTLA-4, [A1] [A2] or both, significantly improved tumor-free survival in both the HER2/neu transgenic breast cancer and the Panc02 metastatic pancreatic cancer mouse models. Using flow cytometry, gene expression profiling, and ex vivo functional assays, we characterized populations of tumor-infiltrating lymphocytes (TILs) and MDSCs, as well as their functional capabilities. We showed that addition of ENT to checkpoint inhibition led to significantly decreased suppression by granulocytic-MDSCs in the TME of both tumor types. We also demonstrated an increase in activated granzyme-B–producing CD8+ T effector cells in mice treated with combination therapy. Gene expression profiling of both MDSCs and TILs identified significant changes in immune-related pathways. In summary, addition of ENT to ICI significantly altered infiltration and function of innate immune cells, allowing for a more robust adaptive immune response. These findings provide a rationale for combination therapy in patients with immune-resistant tumors, including breast and pancreatic cancers.
2018-10-10 | GSE121030 | GEO
Project description:We conducted a single-center, open-label, Simon two-stage, phase II study of entinostat in combination with the PD1 inhibitor nivolumab in patients with advanced pancreatic ductal adenocarcinoma. Patients received oral entinostat 5 mg once a week. After a 14-day lead-in with entinostat monotherapy, patients concurrently receive entinostat 5 mg orally once a week plus nivolumab 240 mg intravenously until the time of progression or unacceptable toxicities.
2024-07-29 | GSE248014 | GEO
Project description:CUT&Tag seq of HK16ac in TS(trophoblast stem cells), STB-D1(TS cells culture in STB medium for syncytialization one day), STB-D4(TS cells culture in STB medium for syncytialization 4 day), STB-D4 treated with oxamate(TS cells culture in STB medium for syncytialization 4 day and treated with oxamate), STB-D4 treated with oxamate and acetate(TS cells culture in STB medium for syncytialization 4 day and treated with oxamate and acetate). we explored the relationship between glycolysis and syncytializaion.
2024-08-02 | GSE246639 | GEO
Project description:We presents a single-nucleus transcriptome analysis in the Wild-type(N2), ent-1KO mutant, ent-2KO mutant and ent-1KO;ent-2KD mutants which revealed that genes involved in purine metabolism were specifically up-regulated in the germline, suggesting the possible specificity of ENT-1/2 in transporting purine nucleosides.
2024-12-20 | GSE265917 | GEO
Project description:Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. The patients with MDS, chronic myelomonocytic leukemia (CMMoL), and high risk AML were treated with sequential administration of methylation inhibitor drugs (5AC and entinostat). To study gene expresion regulation in treated patients, microarray analysis was done on RNA samples extracted from CD34+ cells from 18 patients before and 15 days after treatment using Affymetrix U133Plus2.0. 18 enrolled patients were treated with sequential administration of 5AC and entinostat and microarray analysis were done on RNA samples from CD34+ cells before and 15 days after treatment using Affymetrix U133Plus2.0. One chip was used for one sample and there was no technical replicates. Twelve pairs of day 0 and day 15 specimens passed quality control for hybridization and RNA integrity. A list of differentially regulated genes was created after GC-RMA normalization by t-test paired using a 1.5 fold cut-off with p<0.005.
2009-06-20 | E-GEOD-16625 | biostudies-arrayexpress
Project description:Iron is essential for many cellular processes and is required by bacteria for replication. To acquire iron from the host, pathogenic Gram-negative bacteria secrete siderophores, including Enterobactin (Ent). However, Ent is bound by the host protein Lipocalin 2 (Lcn2), preventing bacterial reuptake of aferric or ferric Ent. In two experiments we treated A549 (lung cancer cell line) cells with Lcn2, Ent, and iron, alone and in combination. In experiment 1, biological duplicates of 4 conditions were used: PBS control, Lcn2, Lcn2+Ent, and Lcn2+Ent+iron. In experiment 2, 4 biological replicates of 4 conditions were used: PBS control, Ent, iron, and Ent+iron. Targets made from the samples were hybridized to Affymetrix Human Gene 1.0 ST arrays to measure transcript abundances. The RMA algorithm was used to estimate transcript levels. Replicate samples were exchangeable, so we fit one-way ANOVA models to log2-transformed data separately to each experiment, and tested for pairwise differences between groups in each experiment, as well as asking if the Ent vs. PBS differences were larger or smaller than the Ent+iron vs. iron differences (Ent by iron interactions). We report results for 29096 probe-sets that were not annotated as positive or negative controls on the array. A supplementary Excel workbook is provided that contains the estimated expression level, some probe-set annotation, and simple statistical analysis for each probe-set. It may be convenient for some users, however obtaining newer probe-set annotation may be advisable. A549 (ATCC CCL-185) cells, a human type II pneumocyte cell line, were cultured in F12K (Invitrogen, Carlsbad, CA) media supplemented with 10% fetal bovine serum (Invitrogen) and 1:100 penicillin streptomycin (Invitrogen). 24-well plates were seeded with A549 cells at a concentration of 35000 cells/well. After two days, cells were weaned from serum and antibiotics overnight. Cells were then stimulated overnight with the indicated combinations of 50 uM Ferric ammonium citrate (FAC) (Sigma, St. Louis, MO), 50 um Ent (Sigma or EMC Microcollections, Tubingen, Germany), and/or 25 uM lipocalin 2 (Lcn2) in F12K media lacking serum or antibiotics. Prior to incubation with cells, siderophore-Lcn2 complexes were prepared by sequential incubation at room temperature of FAC and Ent for 30 minutes followed by addition of Lcn2 and incubation for an additional 30 minutes. In experiment 1, 2 biological replicates of each of these 4 conditions were grown: PBS, 25 uM lipocalin 2 (Lcn2), a combination of 25 uM Lcn2 with 50 uM Enterobactin (Ent), and a combination of Lcn2, Ent and 50 uM Ferric Ammonium Citrate (FAC). In experiment 2, 4 biological replicates of each of these 4 conditions were grown: PBS, 50 uM Ent, 50 uM FAC, and a combination of 50 uM Ent and 50 uM FAC. Cells were harvested and RNA was extracted using an miRNeasy Mini Kit (Qiagen). Biotinylated cDNA targets were prepared according to the Ambion WT expression kit protocol from 150 ng total RNA. There are no batches within each experiment - the samples in each group are exchangeable. Targets were hybridized to Affymetrix Human Gene 1.0 ST arrays. Arrays were scanned and quantified by usual procedures, and transcript abundances for 29096 non-control probe-sets estimated by an RMA algorithm.
2014-07-03 | E-GEOD-54962 | biostudies-arrayexpress
Project description:HPV-associated malignancies continue to present a major health concern despite the development of prophylactic vaccines. Standard therapies offer limited benefit to patients with advanced stage disease. Despite improved outcomes with PD-1 targeted therapies, treatment resistance and modest response rates highlight a significant unmet need to develop novel therapies for these patients. PDS0101 (designated HPV vaccine) is a liposomal nanoparticle HPV16-specific therapeutic vaccine that has been shown to generate strong HPV-specific responses in pre-clinical and clinical studies. Here we assess the efficacy of this HPV vaccine in combination with the tumor-targeting immunocytokine NHS-IL12 (PDS01ADC), plus either aPD-1 or the class I histone deacetylase (HDAC) inhibitor Entinostat. Mice bearing HPV16+, aPD-1 refractory TC-1 and mEER tumors were treated with HPV vaccine, NHS-IL12, and either aPD-1 or Entinostat to determine anti-tumor efficacy and survival benefits. A comprehensive analysis of the tumor microenvironment was performed using flow cytometry, multiplex immunofluorescence, chemokine and cytokine assessment, and scRNAseq with TCR enrichment. Combination of HPV vaccine and NHS-IL12 with either Entinostat or aPD-1 yields significant anti-tumor activity and prolonged survival in aPD-1 refractory models of HPV16+ cancer, with superior activity employing Entinostat versus aPD-1 combination. Entinostat triple therapy increased overall and HPV16-specific tumor CD8+ T cell infiltration with heightened cytotoxicity. TCR sequencing revealed a CD8+ T cell clone unique to vaccine-treated cohorts, which displayed an enriched cytotoxic transcriptional profile with triple therapy. These effects were parallelled by strong differentiation of tumor-associated macrophages (TAMs) towards proinflammatory, anti-tumor M1-like cell states. Single-cell transcriptomic analysis indicated all three agents were required for highest modulation of both CD8+ T cells and TAMs conducive to tumor control. A biomarker signature reflecting the pre-clinical findings was found to be associated with improved survival in patients with HPV-associated malignancies. Together, these findings provide a rationale for the combination of HPV vaccine, NHS-IL12, and Entinostat in the clinical setting for patients with HPV16-associated malignancies.
2025-05-07 | GSE295238 | GEO