Disease-specific exhaustion features and PD-1 immunotherapy responsiveness of antigen-specific CD8+ T cells at single-cell resolution
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PROVIDER: PRJNA639849 | ENA |
REPOSITORIES: ENA
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Project description:We reported the CD8+ T cell exhaustion differences between chronic viral infection and tumor regarding their transcriptomic and epigenetic landscapes, immune checkpoint blockade responsiveness and underlying molecular mechanisms by using bulk RNA-seq, single-cell RNA-seq and single-cell ATAC-seq.
2022-11-29 | GSE152618 | GEO
Project description:Disease-specific exhaustion features and PD-1 immunotherapy responsiveness of antigen-specific CD8+ T cells at single-cell resolution [scRNA-seq]
| PRJNA639836 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-11-29 | GSE152628 | GEO
Project description:Epigenetic regulation drives the differentiation of T cells into phenotypically stable subsets including a dysfunctional state termed exhaustion, the presence of these epigenetically distinct T cells in tumors make them non-responsive to checkpoint blockade. Cancer immunotherapies restoring T cell function have transformed cancer treatment by preventing immune evasion of tumor cells allowed by T cell exhaustion. However, some patients develop resistance to immunotherapy or do not respond. Recent literature has demonstrated that epigenetic regulation governs the transition from effector to exhausted T cells. Here, we describe a novel antigen-specific assay for T-cell exhaustion that produces T cells biologically and epigenetically similar to their in vivo exhausted counterpart. We perform a CRISPR KO screen for epigenetic regulators of the human genome and validate Ikaros as a driver of T-cell exhaustion. We determined that the Ikaros degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers by preserving activity of key transcription factors AP-1, NF-κB and NFAT using transcription factor footprinting analysis. Thus, our study uncovers a role for Ikaros, degraded by the drug iberdomide, as a driver of T-cell exhaustion.
2024-09-02 | GSE244180 | GEO
Project description:Epigenetic regulation drives the differentiation of T cells into phenotypically stable subsets including a dysfunctional state termed exhaustion, the presence of these epigenetically distinct T cells in tumors make them non-responsive to checkpoint blockade. Cancer immunotherapies restoring T cell function have transformed cancer treatment by preventing immune evasion of tumor cells allowed by T cell exhaustion. However, some patients develop resistance to immunotherapy or do not respond. Recent literature has demonstrated that epigenetic regulation governs the transition from effector to exhausted T cells. Here, we describe a novel antigen-specific assay for T-cell exhaustion that produces T cells biologically and epigenetically similar to their in vivo exhausted counterpart. We perform a CRISPR KO screen for epigenetic regulators of the human genome and validate Ikaros as a driver of T-cell exhaustion. We determined that the Ikaros degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers by preserving activity of key transcription factors AP-1, NF-κB and NFAT using transcription factor footprinting analysis. Thus, our study uncovers a role for Ikaros, degraded by the drug iberdomide, as a driver of T-cell exhaustion.
2024-09-02 | GSE244162 | GEO
Project description:Epigenetic regulation drives the differentiation of T cells into phenotypically stable subsets including a dysfunctional state termed exhaustion, the presence of these epigenetically distinct T cells in tumors make them non-responsive to checkpoint blockade. Cancer immunotherapies restoring T cell function have transformed cancer treatment by preventing immune evasion of tumor cells allowed by T cell exhaustion. However, some patients develop resistance to immunotherapy or do not respond. Recent literature has demonstrated that epigenetic regulation governs the transition from effector to exhausted T cells. Here, we describe a novel antigen-specific assay for T-cell exhaustion that produces T cells biologically and epigenetically similar to their in vivo exhausted counterpart. We perform a CRISPR KO screen for epigenetic regulators of the human genome and validate Ikaros as a driver of T-cell exhaustion. We determined that the Ikaros degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers by preserving activity of key transcription factors AP-1, NF-κB and NFAT using transcription factor footprinting analysis. Thus, our study uncovers a role for Ikaros, degraded by the drug iberdomide, as a driver of T-cell exhaustion.
2024-09-02 | GSE244183 | GEO
Project description:Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. While immune checkpoint blockade and adoptive T cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden-related pathway changes that are conducive to T-cell exhaustion. We then determined if microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. Experimental Design: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor (HDACi) MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. Results: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively up-regulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2-STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed towards terminal effector cell-like CD44+ Tim-3hi TCF1- CD127- KLRG1+ differentiation. Conclusion: Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation.
2023-07-29 | GSE238233 | GEO
Project description:Targeting SNX9 rescues CD28-mediated T cell exhaustion for cancer immunotherapy
| PRJNA786531 | ENA
Project description:Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. While immune checkpoint blockade and adoptive T cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden-related pathway changes that are conducive to T-cell exhaustion. We then determined if microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. Experimental Design: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor (HDACi) MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. Results: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively up-regulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2-STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed towards terminal effector cell-like CD44+ Tim-3hi TCF1- CD127- KLRG1+ differentiation. Conclusion: Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation. We used whole transcriptome arrays (Clariom D) to determine the effect of MS-275 on exhausted T cells in ACT+/-MS-275-treated mice
2023-07-29 | GSE238222 | GEO
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