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Disease-specific exhaustion features and PD-1 immunotherapy responsiveness of antigen-specific CD8+ T cells at single-cell resolution [scRNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE152618 | GEO | 2022/11/29

REPOSITORIES: GEO

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Disease-specific exhaustion features and PD-1 immunotherapy responsiveness of antigen-specific CD8+ T cells at single-cell resolution

Project description:Disease-specific exhaustion features and PD-1 immunotherapy responsiveness of antigen-specific CD8+ T cells at single-cell resolution

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Disease-specific exhaustion features and PD-1 immunotherapy responsiveness of antigen-specific CD8+ T cells at single-cell resolution

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

2022-11-29 | GSE152628 | GEO

Disease-specific exhaustion features and PD-1 immunotherapy responsiveness of antigen-specific CD8+ T cells at single-cell resolution [scRNA-seq]

Project description:Disease-specific exhaustion features and PD-1 immunotherapy responsiveness of antigen-specific CD8+ T cells at single-cell resolution [scRNA-seq]

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Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [scATAC-seq]

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.

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Degradation of Ikaros prevents epigenetic progression of T cell exhaustion in novel antigen-specific assay [scRNA-seq]

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Transcrpition landscapes of CD4 T cell exhaustion in response to transplant antigen

Project description:We report the gene profiles of exhaustion-like and effector-like CD4 T cells in response to transplant antigen. To obain the transcprition landscapes of exhuasted and effector CD4 T cells , we generated RNA-seq of TCR transgeneic TEa cells in response to abundant IE-α antigen (exhuast) or to Balb/c skin grafts (effector). We find that TEa cells upregulated the expression level of key exhaustion genes, including Pdcd1, Tox, lag3, Cd38, Cd200, as well as downregulated the expression levels of effector genes Ifng, Gzmb, Prf1, Tbx21, Il2ra, Fasl and Klrg1. This study provides a better understanding of CD4 T cell exhaustion in response to alloantigen.

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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).

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2024-01-07 | E-MTAB-13658 | biostudies-arrayexpress

Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8+ T Cell Response in Hepatocellular Carcinoma.

Project description:Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host's antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8+ T cells is discussed in this review.

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