IL-7-primed bystander CD8 tumor-infiltrating lymphocytes optimize the antitumor efficacy of T-cell engager immunotherapy in solid tumors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA994499 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25265327.fastq.gz | Fastqsanger.gz | |||
| SRR25265328.fastq.gz | Fastqsanger.gz | |||
| SRR25265329.fastq.gz | Fastqsanger.gz | |||
| SRR25265330.fastq.gz | Fastqsanger.gz | |||
| SRR25265331.fastq.gz | Fastqsanger.gz |
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Project description:Bispecific T-cell engagers (TCEs) show promising clinical efficacy in blood tumors, but their application to solid tumors with immunosuppressive environments remains challenging. Here, we show that Fc-fused IL-7 (rhIL-7-hyFc) changes the intratumoral CD8 T cell landscape, allowing TCE-immunotherapy to function effectively in solid tumors. In order to explore the transcriptomic changes induced by rhIL-7-hyFc or a combination of rhIL-7-hyFc and TCE treatment at the clonal level, we performed scRNA/TCR-seq.
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2025-09-03 | GSE306797 | GEO
Project description:Background: The radiation bystander response is an important component of the overall response of cells to radiation and critical to understanding health risks of radiation exposure to humans. The mechanism of radiation response includes inter-cellular signaling and intra-cellular communication by which the bystander signal is propagated. Methods: We measured the bystander response to 1Gy a-particle radiation in Mrad9-/- mouse stem cells and H1299shRAD9 cells, using chromosomal aberration and micronucleus formation as DNA damage endpoints. In the H1299 model we used whole genome microarray analyses to profile the transcriptome of irradiated and bystander cells. Results: We investigated the role of RAD9 in the bystander response and showed that depletion or mutation of RAD9 had an effect of increasing chromosomal structural damage as well as micronucleus formation in bystander cells. The enhancement of the damage effect correlated strongly with a transcriptomic response in critical pathways. RAD9 depletion affected many pathways in the cell, including the UV-MAPK pathway, involving p38MAPK members, STAT1 and PARP1 at the mRNA levels. There was an overall reduction of RNA biogenesis of gene members of this pathway suggesting that perhaps these signaling pathways do not function optimally after RAD9 depletion. Using network analysis we found there may be differential activation of transcriptional regulators between the irradiated and bystander cells involving the SP1 and NUPR1 transcription factors. Network analysis also suggested that HIF1a (Hypoxia induced factor 1a) activation could be a negative predictor of the bystander effect and perhaps that local hypoxic stress observed by cells that are directly exposed to radiation may predict whether or not they will elicit a bystander response. Gene expression in H1299 cells was measured at 4 hours after exposure to 1 Gy a-particles. There were two groups based on RAD9 status, RAD9 normal and RAD9 depleted by siRNA. In each of these groups, sham irradiated, direct irradiated cells for positive bystanders, positive bystanders, direct irradiated cells for negative bystanders and negative bystanders; were identified based on micronucleus responses. Five biological replicates were analyzed for each experimental group.
2014-10-07 | E-GEOD-55869 | biostudies-arrayexpress
Project description:Radiation affects tissue and cellular integrity at the level of DNA, protein and metabolites of the cell and extracellular space. The effects of radiation are not limited to targeted cells and tissue and radiation induced bystander effects are significant to exposed individuals in accidental or therapeutic situations. These non-targeted effects of radiation have been studied extensively at the low dose range where they appear to have adverse effects on cells and surrounding environments. The requirement of cellular contact and shared fluid media has been established as critical to the bystander effect yet there is not much known about the actual signaling mechanism and its ability to transmit the damaging effect over space and time. Experimental cell types and context within the tissue are also quite important to the nature and extent of this bystander effect and must be considered when drawing parallels at the organismal level. Our approach was to use a genomic level analysis of global mRNA expression in primary lung fibroblast cells to understand the cellular triggers and mechanism of the bystander effect. Gene ontology and pathway analyses suggested that the p53 induced transcriptional response appears muted in bystanders while cytokine and cell signaling mechanisms such as those controlled by NFkB and p38 MAPK are highly active in both populations. We validated a large number of genes that are significantly changed at 4hrs after irradiation in both irradiated and bystander populations. We investigated time course gene expression profiles of cyclooxygenase2 (PTGS2), interleukin 8 (IL8) and BCL2 related protein 2 (BCL2A1), as genes that are involved in cellular signaling via the NFkB pathway, which revealed that there is a dramatic response at 0.5hr after irradiation followed by another wave at 4hr in both populations. The induction of interleukins such as cytokine IL8 and chemokine IL6 at the transcriptional level is both early and amplified and if followed by translation and secretion of these proteins could explain the concerted response seen in bystander cells. Our results are the first to show that there is a significant and distinct global response of cellular signaling genes in bystander cells with some genes showing a response as early as 0.5hr after irradiation which implies a fast moving intercellular signal that leads to a concerted response in the irradiated and bystander populations. Keywords: gene expression fold change There are 12 total samples, 4 corresponding biological replicates of IMR90 cells that were not irradiated (control=C), irradiated (alpha=A) and bystander (B)
2008-12-28 | E-GEOD-12435 | biostudies-arrayexpress
Project description:The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is well established. It raises concerns for the interpretation of risks from exposure to low doses of ionizing radiation. Sparse data exists about the bystander signaling mechanisms and the ability to transmit damaging effects both spatially and temporally. To understand early signaling and cellular changes in bystanders, we have measured global gene expression 30 minutes after direct and bystander exposure to alpha particle in primary human lung fibroblasts. Gene ontology and pathway analyses suggested that the earliest measured changes at 30 minutes after treatment are in cell structure, motility and adhesion categories and a significant number of genes belong to the category of inflammation and cell-to-cell communication. We investigated time course gene expression profiles of matrix metalloproteinases 1 and 3 (MMP1 and MMP3), chemokine ligands 2, 3 and 5 (CXCL2, CXCL3 and CXCL5), interleukins 1a, 1b, 6 and 33 (IL1A, IL1B, IL6 and IL33) growth differentiation factor 15 (GDF15) and superoxide dismutase2 (SOD2) by real time quantitative PCR. These encode proteins involved in cellular signaling via the NFkappaB pathway and time course of mRNA levels revealed an increased response at 30 minutes after irradiation followed by another wave at 4 to 6 hours. We also investigated protein modifications in the AKT-GSK-3 signaling pathway and found that in irradiated cells AKT and GSK3beta are hyper-phosphorylated at 30 minutes and this effect is maintained until 4 hours after exposure. In bystanders there is a similar response with a delay of 30 minutes. In irradiated cells, inactivated GSK3beta led to decreased phosphorylation of beta-catenin. Our results are the first to show that the radiation induced bystander signal can induce a widespread gene expression response as early as 30 minutes after exposure and that these changes are accompanied by protein modification of signaling modules such as AKT and GSK3beta. There are 12 total samples, 4 corresponding biological replicates of IMR90 cells that were not irradiated (control=C), irradiated (alpha=A) and bystander (B), cells were harvested 0.5 hr after treatment
2010-07-21 | E-GEOD-18760 | biostudies-arrayexpress
Project description:Immunotherapy strategies in acute myeloid leukemia remain limited. CD123 is a promising target as it is overexpressed in myeloid blasts. This preclinical work investigates possible synergy of CD123 T cell engager and dendritic cell based vaccine, which can induce the expansion of leukemia specific T cells. Efficacy of combination therapy was evaluated in a patient-derived xenograft model and the infused T cells were later collected for single cell rnaseq to determine effects on gene expression pathways and clonality. In the present study, we demonstrated that the combination of DC/AML fusion vaccine and a CD123 T cell engager SAR440234 led to an increase in tumor specific T cell immunity and enhanced anti-leukemia effect in vitro. Furthermore, the combination treatment was shown to increase cytotoxic T cell subsets and clonotypic expansion and eradicate disease in vivo. Thus the combination of T cell engager and vaccination or adoptive T cell transfer is a novel approach that merits further investigation in clinical trials.
2025-06-06 | GSE265780 | GEO
Project description:The radiation bystander effect is an important component of the overall biological response of tissues and organisms to ionizing radiation. Little is known about the contribution of genome level changes in neighboring bystander cells to tissue and organ stress after irradiation. The timing of these changes is critical in the physiological context and these questions can only be answered by studying signaling and global transcriptomics in a chronological way. Here, we present a strategy to identify different biologically important signaling modules that act in concert in the radiation and bystander responses. We used time series gene expression analysis of normal human fibroblast cells measured at 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after exposure to radiation coupled with a novel clustering method targeted to short time series, Feature Based Partitioning around medoids Algorithm (FBPA), to look for genes that were potentially co-regulated. This method uses biologically meaningful features of the expression profile and dimension augmentation to address the analysis of sparse data sets such as ours. We applied FBPA and Short Time series Expression Miner (STEM) to the same datasets and present the results of our comparisons using computational metrics as well as biological enrichment. Enrichment showed that gene expression in irradiated cells fell into broad categories of signal transduction, cell cycle/cell death and inflammation/immunity; but only FBPA clustered functions well. In bystander cells, the gene expression response was also broadly categorized into functions associated with cell communication and motility, signal transduction and inflammation; but neither STEM nor FBPA separated biological functions as well as in irradiated samples. Network analysis revealed that p53 and NF-kappaB were central players in gene expression in both irradiated and bystander gene clusters. Analysis of individual clusters also suggested new regulators of gene expression in the radiation and bystander response that may act at the epigenetic level such as histone deacetylases (HDAC1 and HDAC2) and methylases (KDM5B) that can act as strong transcription repressors. Based on these results, we propose a novel time series clustering method, FBPA, as a powerful approach that can be applied to sparse data sets (including genomic profiling data), where the choice of features selected for clustering and stringent statistical outcome analysis can augment our knowledge of the underlying cellular mechanisms in biological processes. There are 72 total samples, 4 corresponding biological replicates of IMR90 cells that were not irradiated (control=C), irradiated (alpha=A) and bystander (B), cells were harvested at 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after treatment
2011-01-14 | E-GEOD-21059 | biostudies-arrayexpress
Project description:With the immunodeficient mouse model coupled with TBI and coculture system, we found that the radiation-induced bystander effect also occurred to human hematopoietic cells. The long-term hematopoietic reconstitution of bystander human HSCs was significantly decreased, and the colony-forming ability of bystander human hematopoietic progenitor cells was reduced. Further study found that the bystander human hematopoietic cells initiated enhanced DNA damage responses (DDRs), cell cycle arrest and p53-dependent apoptosis, mainly due to oxidative stress. Moreover, some antioxidants could mitigate this bystander effect with different efficacies both in vitro and in vivo.
2021-03-29 | GSE149649 | GEO
Project description:We have recently investigated the response of irradiated and bystander fibroblasts to heavy ions in confluent cultures exposed randomly to broadbeam and selectively to precision microbeam that target a predefined fraction of cells with counted number of particle(s), respectively, and found the difference in the time course of apoptosis induction and p53 phosphorylation between irradiated and bystander cells [Hamada MR2008]. In the present investigation, to further scrutinize the underpinnings of their temporally distinct responses, we set out to examine the gene expression changes in irradiated and bystander fibroblasts at a genome-wide level with the microarray analysis under the same experimental condition. We demonstrate that the gene expression profiles of bystander cells are substantially different from those of heavy ion-irradiated cells. Keywords: bystander effect, hour-time course cell number dependency, irradiation-dose response
2008-09-02 | GSE8993 | GEO
Project description:To understand the cellular response of bystander cells, we performed a 2D gel-based proteomic study of the chondrocyte receiving the conditioned medium of low dose irradiated chondrosarcoma cells. The proteomic analysis of the bystander chondrocytes highlighted 20 proteins spots that were significantly modified at low dose, implicating several cellular mechanisms, such as oxidative stress responses, cellular motility and exosomes pathways. Several of these candidates and cellular mechanisms were confirmed by functional analysis, such as 8-oxodG quantification, western blot and wound-healing migration tests.
2021-09-10 | PXD025187 | Pride