Dynamic chromatin regulatory landscape of human CAR T cell exhaustion [ATAC-seq]
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ABSTRACT:
PROVIDER: PRJNA714409 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13961024_1.fastq.gz | Fastqsanger.gz | |||
| SRR13961024_2.fastq.gz | Fastqsanger.gz | |||
| SRR13961025_1.fastq.gz | Fastqsanger.gz | |||
| SRR13961025_2.fastq.gz | Fastqsanger.gz | |||
| SRR13961026_1.fastq.gz | Fastqsanger.gz |
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Project description:Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found widespread, dynamic changes in chromatin accessibility and 3D chromosome conformation preceding changes in gene expression, notably at loci proximal to exhaustion-associated genes such as PDCD1, CTLA4, and HAVCR2, and increased DNA motif access for AP-1 family transcription factors, which are known to promote exhaustion. Although T cell exhaustion has been studied in detail in mouse, we find that the regulatory networks of T cell exhaustion differ between the species and involve distinct loci of accessible chromatin and cis-regulated target genes in human CAR T cell exhaustion. Deletion of exhaustion-specific candidate enhancers of PDCD1 suppress the expression of PD-1 in an in vitro model of T cell dysfunction and in HA-28z CAR T cells, suggesting enhancer editing as a path forward in improving cancer immunotherapy.
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Project description:Dynamic chromatin regulatory landscape of human CAR T cell exhaustion
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Project description:Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found widespread, dynamic changes in chromatin accessibility and 3D chromosome conformation preceding changes in gene expression, notably at loci proximal to exhaustion-associated genes such as PDCD1, CTLA4, and HAVCR2, and increased DNA motif access for AP-1 family transcription factors, which are known to promote exhaustion. Although T cell exhaustion has been studied in detail in mouse, we find that the regulatory networks of T cell exhaustion differ between the species and involve distinct loci of accessible chromatin and cis-regulated target genes in human CAR T cell exhaustion. Deletion of exhaustion-specific candidate enhancers of PDCD1 suppress the expression of PD-1 in an in vitro model of T cell dysfunction and in HA-28z CAR T cells, suggesting enhancer editing as a path forward in improving cancer immunotherapy.
2021-05-01 | GSE168881 | GEO
Project description:Dynamic chromatin regulatory landscape of human CAR T cell exhaustion [HiChIP]
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Project description:Chimeric antigen receptor (CAR) T-cells have not induced meaningful clinical responses in solid tumor indications. Loss of T-cell stemness, poor expansion capacity and exhaustion during prolonged tumor antigen exposure are major causes of CAR T-cell therapeutic resistance. scRNA-sequencing analysis of CAR T-cells from a first-in-human trial in metastatic prostate cancer identified two distinct and independently validated cell states associated with antitumor potency or lack of efficacy. Low levels of the PRDM1 gene encoding the BLIMP1 transcription factor defined highly potent TCF7+CD8+ CAR T-cells, while enrichment of TIM3+CD8+ T-cells with elevated PRDM1 expression predicted poor outcome. PRDM1 single knockout promoted TCF7-dependent CAR T-cell stemness and proliferation resulting in marginally enhanced leukemia control. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of NFAT-driven T-cell dysfunction characterized by compensatory upregulation of NR4A3 and multiple other genes encoding exhaustion-related transcription factors hampered effector function in solid tumors. PRDM1 and NR4A3 combined ablation skewed CAR T-cell phenotypes away from TIM3+CD8+ and toward TCF7+CD8+ to counter exhaustion of tumor-infiltrating CAR T-cells and improve in vivo antitumor responses, effects that were not achieved with BLIMP1 or NR4A3 single disruption alone. These data reveal a novel molecular targeting strategy to enrich stem-like CAR T-cells resistant to exhaustion and underscore dual inhibition of PRDM1/NR4A3 expression or activity as a promising approach to advance adoptive cell immuno-oncotherapy.
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Project description:ATAC-seq was used to study the chromatin landscape of Invitro CD8 T cell exhaustion cells
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Project description:We used ATAC-Seq to define the accessible chromatin landscape in exhausted CD8+ T cells, showed that it is distinct from functional memory CD8+ T cells, and identified an exhaustion-specific enhancer of PD-1. In addition to the murine T cell data, we will provide the ATAC-Seq data used from human T cells in the paper.
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Project description:Cooperative interactions among transcription factors are essential for gene transcription. We previously showed that NFAT and AP-1 (Fos-Jun) transcription factors cooperate to promote the effector functions of T cells, but that under conditions where it is unable to cooperate with AP-1, NFAT imposes a negative feedback programme of T cell hyporesponsiveness (“exhaustion”). Here we show that BATF and IRF4 cooperate to counter T cell exhaustion. Overexpression of Batf in CD8+ 42 T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumour-infiltrating CAR T cells, increased their production of effector cytokines, decreased their expression of inhibitory receptors and the exhaustion-associated transcription factor TOX, and led to the generation of long-lived memory T cells that controlled tumour recurrence. These responses were dependent on the BATF-IRF interaction, since cells expressing a Batf mutant unable to interact with Irf4 did not survive in tumours and did not effectively delay tumour growth. We suggest that BATF overexpression is a therapeutically viable option for improving the anti-tumour responses of CAR TILs, by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.
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Project description:CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of numerous bZIP and IRF transcription factors that have been implicated in inhibitory activity. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in numerous in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.
2019-10-01 | GSE136891 | GEO
Project description:CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of numerous bZIP and IRF transcription factors that have been implicated in inhibitory activity. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in numerous in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.
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