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Dynamic chromatin regulatory landscape of human CAR T cell exhaustion [HiChIP]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168881 | GEO | 2021/05/01

REPOSITORIES: GEO

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Dynamic chromatin regulatory landscape of human CAR T cell exhaustion [ATAC-seq]

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 | GSE168880 | GEO

Single-cell gene expression in CD19-specific and GD2-specific CAR T cells on day 10 in culture.

Project description:Purpose: To compare cell states between CD19-28z and GD2-28z human CAR T cells on day 10 of cell culture. Methods: Human T cells were activated and lentivirally transduced with CD19-28z or GD2-28z CAR constructs and maintained in culture for 10 days, and then delivered to the Stanford Functional Genomics Facility for 3' single-cell RNA-sequencing on the 10X Genomics platform. Results: Comparison of transcription factor profiles by single cell RNA-seq analysis of CD8+ T cells expressing CD19-28z vs. GD2-28z CAR confirmed that the bZIP family members JUN, JUNB, JUND, and ATF4 were among the most differentially expressed and broadly connected in exhausted GD2-28z CAR T cells. Conclusions: This study provides insights into cell states that could explain the underlying differences between highly functional CD19-28z CAR T cells and exhaustion-prone GD2-28z CAR T cells on day 10 in culture.

2019-10-01 | GSE136874 | GEO

CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition.

Project description:The objective of this experiment was to characterized the molecular mechanisms behind the different effects of PD-1 disruption in low affinity (LA) and high affinity (HA) HER2-28z CAR-T cells. The transcriptomic profile of mock and PD-1 KO CAR-T cells following antigen recognition was compared by using the nCounter® CAR-T Characterization Gene Expression Panel (Nanostring). RNA samples were isolated from CAR-T cells generated from three independent donors.

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Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion

Project description:Whether or not human Tregs are susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how a tonic-signaling CAR, which induces Tconv exhaustion, affects human Tregs. We thus sorted naïve Tregs and naïve conventional CD4s and transduced them with a non-TS CAR (CD19) or a TS-CAR (HA).

2022-07-28 | GSE209671 | GEO

ATAC-seq profiling of human Tregs and conventional CD4+ cells that were transduced with a non-tonic signaling (CD19) or a tonic signaling (HA) CAR

Project description:Whether or not human Tregs are susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how a tonic-signaling CAR, which induce Tconv exhaustion, affect human Tregs. We thus sorted naïve Tregs and naïve conventional CD4s and transduced them with a non-TS CAR (CD19) or a TS-CAR (HA).

2023-03-15 | GSE209835 | GEO

RNA-seq profiling of human Tregs and conventional CD4+ cells that were left untransduced or transduced with a non-tonic signaling (CD19) or a tonic signaling (HA) CAR

Project description:Whether or not human Tregs are susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how a tonic-signaling CAR, which induce Tconv exhaustion, affect human Tregs. We thus sorted naïve Tregs and naïve conventional CD4s and either left them untransduced (UT) or transduced them with a non-TS CAR (CD19) or a TS-CAR (HA). After 12 days in culture, we isolated their RNA and did RNA sequencing.

2023-03-15 | GSE153384 | GEO

Genome-wide maps of chromatin state in human primary CAR-T cells [ChIPseq, ATAC-seq]

Project description:We report the transcriptomic and epigentic profile of human primary CD19-28z CAR-T cells.

2022-09-06 | GSE174281 | GEO

Genome-wide maps of chromatin state in human primary CAR-T cells [RNA-seq]

Project description:We report the transcriptomic and epigentic profile of human primary CD19-28z CAR-T cells.

2022-09-06 | GSE174279 | GEO

CAR T cells Overexpressing cJun Are Exhaustion-Resistant and Mediate Enhanced Antitumor Activity

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 | GSE136853 | GEO

CAR T cells Overexpressing cJun Are Exhaustion-Resistant and Mediate Enhanced Antitumor Activity

2019-10-01 | GSE136796 | GEO

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