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CD19-CAR T cells undergo exhaustion epigenetic programming in patients with acute lymphoblastic leukemia

ABSTRACT: CD19-CAR T cells undergo exhaustion epigenetic programming in patients with acute lymphoblastic leukemia

PROVIDER: PRJNA778264 | ENA |

REPOSITORIES: ENA

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CD19-CAR T cells undergo exhaustion epigenetic programming in patients with acute lymphoblastic leukemia

Project description:Zebley et al. show that CD8+ CD19-CAR T cells undergo genome-wide DNA methylation changes during an anti-tumor response in patients with B-cell acute lymphoblastic leukemia (ALL). Post-infusion CAR T cell differentiation involves acquisition of DNA methylation programs associated with effector function, repression of memory potential, and transition toward exhaustion.

2021-11-08 | GSE188325 | GEO

CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia.

Project description:CD19-CAR T cell therapy has evolved into the standard of care for relapsed/refractory B cell acute lymphoblastic leukemia (ALL); however, limited persistence of the CAR T cells enables tumor relapse for many patients. To gain a deeper understanding of the molecular characteristics associated with CAR T cell differentiation, we performed longitudinal genome-wide DNA methylation profiling of CD8+ CD19-CAR T cells post-infusion in ALL patients. We report that CAR T cells undergo a rapid and broad erasure of repressive DNA methylation reprograms at effector-associated genes. The CAR T cell post-infusion changes are further characterized by repression of genes (e.g., TCF7 and LEF1) associated with memory potential and a DNA methylation signature (e.g., demethylation at CX3CR1, BATF, and TOX) demarcating a transition toward exhaustion-progenitor T cells. Thus, CD19-CAR T cells undergo exhaustion-associated DNA methylation programming, indicating that efforts to prevent this process may be an attractive approach to improve CAR T cell efficacy.

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

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

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

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

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

Single-cell analysis of CD19-specific CAR T cell treatment of relapsed/refractory CD19+ acute lymphoblastic leukemia

Project description:Single-cell analysis of CD19-specific CAR T cell treatment of relapsed/refractory CD19+ acute lymphoblastic leukemia

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Project description:Single-cell analysis of CD19-specific CAR T cell treatment of relapsed/refractory CD19+ acute lymphoblastic leukemia

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