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De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation

ABSTRACT: De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation

PROVIDER: PRJNA388482 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5629710.fastq.gz	Fastqsanger.gz
	SRR5629710_1.fastq.gz	Fastqsanger.gz
	SRR5629710_2.fastq.gz	Fastqsanger.gz
	SRR5629711.fastq.gz	Fastqsanger.gz
	SRR5629711_1.fastq.gz	Fastqsanger.gz

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De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation [WGBS]

Project description:De novo DNA methylation establishes T cell exhaustion and inhibits PD-1 blockade-mediated T-cell rejuvenation.

2017-06-30 | GSE99450 | GEO

De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation [expression]

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.

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De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation.

Project description: Not available

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De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-06-30 | GSE99451 | GEO

Tumor-Infiltrating Myeloid Cells Confer de novo Resistance to PD-L1 Blockade through EMT-stromal and Tgf-beta Dependent Mechanisms

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

Single-cell RNAseq of α-PD-1 relapsing YUMM2.1 tumours subsequently treated with PARP14i in vivo

Project description:PD-1 signalling blockade is highly effective at restoring immune surveillance and treating melanoma. However, redundant immune homeostatic mechanisms driven by chronic IFNγ signalling can lead to ongoing immune evasion and acquired resistance. PARP14 mediates IFNγ-driven resistance, and prolongs responsiveness to PD-1 blockade in preclinical models. Here we present a single cell RNAseq of immune cells from α-PD-1 relapsing mouse tumours, following subsequent PARP14i treatments alone and in combination with α-PD-1. Our findings highlight a robust PARP14i gene signature associated with improved patient survival, suggesting its potential to enhance PD-1 blockade efficacy.

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Mus musculus

Project description:De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation [WGBS]

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Mus musculus

Project description:De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation [expression]

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Myeloid Niches Sustain Antitumor T Cells and License PD-1 Blockade via CD28 Costimulation

Project description:The local mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TILs) and responsiveness to PD-1 blockade remain partly elucidated. In human ovarian cancer we show that tumor-reactive intraepithelial (ie)CD8+ TILs engaged by antigen are polyfunctional and upregulate PD-1, which restrains their effectiveness. PD-1+ TILs exhibit a continuum of TCR-engaged/exhausted states with variable effector fitness related to CD28 costimulation, which they receive in intraepithelial niches involving myeloid antigen-presenting cells (mAPC). Following PD-1 blockade, activation of TILs requires CD28 costimulation mediated in situ by tumor mAPCs, which is locally enhanced by CTLA-4 blockade. CD40 ligand also amplifies TIL responses in situ, especially in tumors in which mAPCs are not activated. Thus, dysfunctional and exhausted TILs, in a state of TCR engagement but without proper CD28 costimulation by mAPCs in situ, are unlikely to fully benefit from PD-1 blockade.

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2024-12-08 | PXD047616 | JPOST Repository

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