OX40 agonism enhances efficacy of PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum
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ABSTRACT:
PROVIDER: PRJNA797276 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17618764_1.fastq.gz | Fastqsanger.gz | |||
| SRR17618764_2.fastq.gz | Fastqsanger.gz | |||
| SRR17618765_1.fastq.gz | Fastqsanger.gz | |||
| SRR17618765_2.fastq.gz | Fastqsanger.gz | |||
| SRR17618766_1.fastq.gz | Fastqsanger.gz |
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Project description:Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict responses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy.
| S-EPMC10040386 | biostudies-literature
Project description:Immunotherapy effect on T cells in C57BL/6 mice
2023-01-10 | GSE193699 | GEO
Project description:Regulatory T (Treg) maintain the tumor microenvironment in an immunosuppressive state preventing effective anti-tumor immune response. A possible strategy to overcome Treg cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while induced in activated effector T (Teff) cells. OX40 stimulation by the agonist mAb OX86 inhibits Treg cell suppression and boosts Teff cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, which are the most abundant CD4+ populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor IRF1. Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to dendritic cells (DCs). The CD40L/CD40 axis was required for Tem cell-mediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg cell suppression and enhancement of the Tem cell adjuvant effect both concurred to free DCs from immunosuppression and to activate the immune response against the tumor. Total RNA obtained from sorted mouse FoxP3-GFP+ Treg activated in vitro with anti-CD3 in the presence of an OX40-agonist mAb (OX86) or isotype control.
2011-09-25 | E-GEOD-32373 | biostudies-arrayexpress
Project description:An Ox40-cre allele was used for lineage marking of CD4 T cells. Naive T cells that had previously expressed OX40 demonstrated a partially activated phenotype that was distinct from that of the majority of naive T cells. These results are consistent with a minor subpopulation of naive T cells being dependent on strong signaling responses to thymic self ligands. Keywords: T cell population comparison. Characterization of a novel subpopulation of naive T cells. Four types of T cells were sorted from mice (naive, CD44lo, CD44hi and Treg).
2010-04-03 | E-GEOD-13502 | biostudies-arrayexpress
Project description:Analysis of the gene signature of OX40+ Tregs, in comparison to OX40- Tregs and Tconvs, freshly isolated from liver cirrhosis and tumor of chronic HCV patients. Results provide insights into the metabolic mechanisms of Treg proliferation in premalignant/malignant contexts.
2018-06-26 | GSE103523 | GEO
Project description:OX40 is a T cell costimulatory molecule in the tumor necrosis factor receptor (TNFR) superfamily. Unlike other costimulatory molecules, OX40 is not expressed by naive T cells, but its expression is rapidly induced following T cell activation, and OX40 costimulation plays a critical role in cell survival, proliferation, and generation of memory cells. We used ATAC-seq to detail the chromatin accessibility of gene locus of activated CD4 T cells with or without OX40 costimulation in the presence of TGF-β1 and IL-2 and identified distinct classes of genes after OX40 costimulation.
2018-05-18 | GSE114568 | GEO
Project description:Regulatory T (Treg) maintain the tumor microenvironment in an immunosuppressive state preventing effective anti-tumor immune response. A possible strategy to overcome Treg cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while induced in activated effector T (Teff) cells. OX40 stimulation by the agonist mAb OX86 inhibits Treg cell suppression and boosts Teff cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, which are the most abundant CD4+ populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor IRF1. Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to dendritic cells (DCs). The CD40L/CD40 axis was required for Tem cell-mediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg cell suppression and enhancement of the Tem cell adjuvant effect both concurred to free DCs from immunosuppression and to activate the immune response against the tumor.
2011-09-26 | GSE32373 | GEO
Project description:We've recently shown that we can accelerate disease in a model of SLE (the NZB/W F1 model) using an anti-Ox40 mAb treatment regimen. The disease acceleration is rapid (within 2 weeks) but its unclear, mechanistically, how OX40 functions to promote disease. To that end we want to perform RNASeq on the sorted OX40-expressing CD4 T cells during treatment to understand how they function in response to OX40 signaling in vivo
2017-08-18 | GSE99646 | GEO
Project description:Methods: To better understand the role of OX40 in the regulation of monocyte activation and polarization, OX40/Fc- or control IgG-treated liver monocytes were compared in a transcriptome sequencing study. Total RNA was isolated from FACS-separated hepatic monocytes. Transcriptome sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Sequences were aligned to the reference genome with TopHat and processed with Cufflinks, which quantifies each transcript in each sample using reference annotations produced bythe University of California Santa Cruz UCSC. Differentially expressed genes with a fold change of >=2.0 and padj < 0.05 between OX40 treated and control monocytes were submitted to GO and KEGG enrichment analysis, which uses unbiased methods to assess pathway enrichment. Results: Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that upregulated genes from OX40-stimulated monocytes are involved in inflammatory response; cytokine production regulation; lipid, cytokine and bacteria responses; innate immune response; enhanced cellular response to cytokines and the cytokine-cytokine receptor interaction; and the phagosome and chemokine signaling pathway, among others. Compared to control monocytes, OX40/Fc-treated monocytes exhibited upregulated levels of cytokines (Tnf, Il1a, Il1b, Il6 and Il12a), cytokine receptors (Il1rl1, Il2r, Il18r and Il23r), chemokines (Ccl3, Ccl4, Ccl22, Cxcl1, Cxcl2, Cxcl10 and Cx3cl1), chemokine receptors ( Ccrl2, Cxcr5 and Cxcr6) and antigen processing and presentation molecules (Cd40, Cd80, Cd86, Tlr1, Tlr2, and Ox40l). The coordinated action of various inflammatory modulators, signaling molecules, and transcription factors, including Nlrp3, Tank, Jak2, Stat5a, Hif1a, Nos2, Socs3, Mir155hg and Pparg, was determined to be involved in the OX40 regulation of monocyte M1 polarization. MyD88, Irf3, Irf5, Stat1, Nod1 and Nod2 may not be involved in OX40-triggered monocyte M1 polarization.
2019-12-31 | GSE105187 | GEO
Project description:An Ox40-cre allele was used for lineage marking of CD4 T cells. Naive T cells that had previously expressed OX40 demonstrated a partially activated phenotype that was distinct from that of the majority of naive T cells. These results are consistent with a minor subpopulation of naive T cells being dependent on strong signaling responses to thymic self ligands. Keywords: T cell population comparison. Characterization of a novel subpopulation of naive T cells.
2009-09-22 | GSE13502 | GEO