De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation
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ABSTRACT:
PROVIDER: PRJNA388482 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:De novo DNA methylation establishes T cell exhaustion and inhibits PD-1 blockade-mediated T-cell rejuvenation.
2017-06-30 | GSE99450 | GEO
Project description:De novo DNA methylation establishes T cell exhaustion and inhibits PD-1 blockade-mediated T-cell rejuvenation. Expression profiling of chronically stimulated WT and Dnmt3a cKO antigen-specific CD8 T cells.
2017-06-30 | GSE99449 | GEO
Project description:Immune-checkpoint-blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA-methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells, and approaches to reverse these programs improved T cell responses and tumor control during ICB. These data establish de novo DNA-methylation programming as a regulator of T cell exhaustion and barrier of ICB-mediated T cell rejuvenation.
| S-EPMC5568784 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-06-30 | GSE99451 | GEO
Project description:Most bladder cancers are poorly responsive to immune checkpoint blockade (ICB) of PD-L1. Thus, there is a need to define mechanisms of de novo resistance including contributions from tumor infiltrating immune cells. In this study, we used single-cell transcriptional profiling to map and define infiltrating myeloid cells in 10 human bladder tumors. Human data sets were qualitatively compared with myeloid data sets from the carcinogen (BBN) induced mouse model of bladder cancer which we have demonstrated to be poorly responsive to PD-L1 blockade. We previously established a signature of acquired ICB resistance which we apply here to new human and murine tumor data sets that have not received prior ICB (or systemic treatment). In doing so, we reveal conservation in EMT-stromal core genes and TGF beta signaling between human and mouse myeloid cells consistent with signatures of de novo ICB resistance. Untreated BBN tumors were highly infiltrated with M0-M2 macrophages, low in T-NK infiltration and modeled a patient subpopulation with poor survival outcome. Concordantly, the combined targeting of TGFb + PD-L1 reverted immune cell exclusion and resulted in increased survival and delayed BBN mouse tumor progression. These data constitute the stromal and myeloid cell populations as providing a coordinate mechanism de novo resistance to PD-L1 blockade in a TGF-beta dependent manner.
2022-10-17 | GSE211388 | GEO
Project description:Proliferative and replicative senescent fibroblasts from aged human donors were reprogrammed towards pluripotency and re-differentiated in fibroblasts and then further analyzed for rejuvenation assessment. Comparison of microarrays were performed by non hierarchical clustering visualized in with Treeview software
2011-12-14 | E-GEOD-27924 | biostudies-arrayexpress
Project description:Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but most patients do not respond. PD-1 blockade “unleashes” CD8 T cells, including those specific for mutation-associated neoantigens (MANA), but factors in the tumor microenvironment can inhibit responses by dampening MANA-specific T cell function. Recent advances in single cell transcriptomics are revealing global T cell dysfunction programs in tumor-infiltrating lymphocytes (TIL). However, the vast majority of TIL do not recognize tumor antigens and little is known about transcriptional programs of true MANA-specific TIL. Here, we use an integrated approach to identify MANA-specific T cell clones using the MANA functional expansion of specific T cells (MANAFEST) assay in neoadjuvant anti-PD-1-treated lung cancers and use their TCR CDR3 as barcodes to track them and analyze their transcriptional programs and function in the tumor microenvironment using single cell RNA sequencing. We find both MANA-and virus-specific clones in TIL and adjacent normal lung, regardless of response status. MANA-specific, influenza (flu)-specific and EBV-specific TIL each have unique transcriptional programs. Most MANA-specific clones are tissue resident memory (TRM) cells, an incompletely activated cytolytic program, including EOMES deficiency, and higher levels of genes encoding T cell inhibitory molecules and Tox2. Notably, MANA-specific T cells express low levels of IL-7R and are functionally less responsive to IL-7 compared with tissue-resident flu-specific clones. MANA-specific clones from anti-PD-1 non-responding tumors express TCR with markedly lower ligand-dependent signaling capability, are largely confined to HOBIThi TRM subsets and coordinately up-regulate genes encoding specific checkpoints, killer inhibitory receptors, and intracellular inhibitors of T cell activation and cytotoxicity. These findings provide mechanistic and potential therapeutic insights into overcoming resistance to PD-1 blockade.
2021-07-21 | GSE176022 | GEO
Project description:Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but most patients do not respond. PD-1 blockade “unleashes” CD8 T cells, including those specific for mutation-associated neoantigens (MANA), but factors in the tumor microenvironment can inhibit responses by dampening MANA-specific T cell function. Recent advances in single cell transcriptomics are revealing global T cell dysfunction programs in tumor-infiltrating lymphocytes (TIL). However, the vast majority of TIL do not recognize tumor antigens and little is known about transcriptional programs of true MANA-specific TIL. Here, we use an integrated approach to identify MANA-specific T cell clones using the MANA functional expansion of specific T cells (MANAFEST) assay in neoadjuvant anti-PD-1-treated lung cancers and use their TCR CDR3 as barcodes to track them and analyze their transcriptional programs and function in the tumor microenvironment using single cell RNA sequencing. We find both MANA-and virus-specific clones in TIL and adjacent normal lung, regardless of response status. MANA-specific, influenza (flu)-specific and EBV-specific TIL each have unique transcriptional programs. Most MANA-specific clones are tissue resident memory (TRM) cells, an incompletely activated cytolytic program, including EOMES deficiency, and higher levels of genes encoding T cell inhibitory molecules and Tox2. Notably, MANA-specific T cells express low levels of IL-7R and are functionally less responsive to IL-7 compared with tissue-resident flu-specific clones. MANA-specific clones from anti-PD-1 non-responding tumors express TCR with markedly lower ligand-dependent signaling capability, are largely confined to HOBIThi TRM subsets and coordinately up-regulate genes encoding specific checkpoints, killer inhibitory receptors, and intracellular inhibitors of T cell activation and cytotoxicity. These findings provide mechanistic and potential therapeutic insights into overcoming resistance to PD-1 blockade.
2021-07-21 | GSE176021 | GEO
Project description:SignificanceMost patients with bladder cancer do not respond to ICB targeting of the PD-L1 signaling axis. Our modeling applied a de novo resistance signature to show that tumor-infiltrating myeloid cells promote poor treatment response in a TGFβ-dependent mechanism.
| S-EPMC9706595 | biostudies-literature
Project description:Proliferative and replicative senescent fibroblasts from aged human donors were reprogrammed towards pluripotency and re-differentiated in fibroblasts and then further analyzed for rejuvenation assessment.
2011-12-14 | GSE27924 | GEO