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Mus musculus

ABSTRACT: Epigenetic inflexibility of exhausted T cells limits durability of reinvigoration by PD-1 blockade

PROVIDER: PRJNA342526 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR4235370_1.fastq.gz	Fastqsanger.gz
	SRR4235370_2.fastq.gz	Fastqsanger.gz
	SRR4235371_1.fastq.gz	Fastqsanger.gz
	SRR4235371_2.fastq.gz	Fastqsanger.gz
	SRR4235372_1.fastq.gz	Fastqsanger.gz

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PD-1 blockade-unresponsive human tumor-infiltrating CD8+ T cells are marked by loss of CD28 expression and rescued by IL-15

Project description:Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8+ T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8+ T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1-induced human T-cell reinvigoration using tumor-infiltrating CD8+ T cells (CD8+ TILs) obtained from non-small cell lung cancer patients. Single cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8+ TILs. Furthermore, we found that human CD28+CD8+, but not CD28–CD8+ TILs, responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 co-stimulation in human CD8+ TILs is dispensable for PD-1 blockade-induced reinvigoration, and loss of CD28 expression rather serve as a marker of anti-PD-1-unresponsive CD8+ TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28–PD-1+CD8+ TILs exhibited characteristics of terminally exhausted CD8+ T cells with low TCF1 expression. Notably, CD28–PD-1+CD8+ TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced proliferation of CD28–PD-1+CD8+ TILs as well as CD28+PD-1+CD8+ TILs. Taken together, we demonstrate loss of CD28 expression as a marker of PD-1 blockade-unresponsive human CD8+ TILs with TCF1– signature and provide mechanistic insights into combining IL-15 with anti-PD-1.

2020-05-01 | GSE145896 | GEO

Expression data from CD8 T cells from LCMV-Clone13 infected mice after two weeks of control or anti-PD-L1 treatment

Project description:Blocking PD-1 can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. One potential advantage of this immunotherapy is durable protection if immune memory can be established. It is unclear, however, whether blocking PD-1 can reprogram TEX into effector (TEFF) or durable memory T cells (TMEM). Here, we found reinvigoration of TEX by PD-L1 blockade caused re-acquisition of some features of TEFF, but minimal memory development. We used microarray analysis to profile exhausted cells from anti-PD-L1 mice after two weeks of treatment to study if PD-L1 blockade caused re-acquistion of some feature of effector or memory cells.

2016-10-31 | GSE86796 | GEO

Dual Relief of T-Lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

Project description:Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in cancer patients could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggests a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor-specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison to their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor-specific CD8 T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated head and neck cancer patients. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.

2020-05-01 | GSE148162 | GEO

4-1BB Co-stimulation Further Enhances Anti-PD-1-Mediated Reinvigoration of Exhausted CD39+ CD8 T Cells from Primary and Metastatic sites of Epithelial Ovarian Cancers

Project description:4-1BB Co-stimulation Further Enhances Anti-PD-1-Mediated Reinvigoration of Exhausted CD39+ CD8 T Cells from Primary and Metastatic sites of Epithelial Ovarian Cancers

2020-11-04 | GSE160705 | GEO

Bidirectional Introgression between Mus musculus domesticus and Mus spretus.

Project description: Not available

| S-EPMC8784167 | biostudies-literature

Epigenetic inflexibility of exhausted T cells limits durability of reinvigoration by PD-1 blockade

Project description:Upon PD-1 pathway blockade,the epigenetic landscape of exhausted cells was only minimally remodeled consistent with lineage commitment and re-exhaustion of these cells over time.

2016-10-31 | GSE86797 | GEO

Mus musculus

Project description:De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation [WGBS]

| PRJNA388487 | ENA

Mus musculus

Project description:De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation [expression]

| PRJNA388486 | ENA

A transcriptionally und functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small cell lung cancer treated with PD-1 blockade

Project description:Evidence from mouse chronic viral infection models suggests that CD8+ T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic, and functional signatures of intratumoral CD8+ T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1-) from non-small cell lung cancer patients. We observed that, PD-1T T cells show a markedly different transcriptional and metabolic profile as compared to PD-1N and PD-1- lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T lymphocytes are impaired in classical effector cytokine production, they produce CXCL13 that mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1T cells was strongly predictive for both response and survival in a small cohort of non-small cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1 bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides novel potential avenues for therapeutic intervention.

2018-05-22 | GSE99531 | GEO

Krüppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T-cells [ATAC-Seq]

Project description:Since exhausted CD8 T-cells are known to have a strong epigenetic imprint, which is a major obstacle for reinvigoration, we investigated whether the induced Klf4 expression could change the epigenetic status of the exhausted CD8 T-cells. For this, we performed ATAC-sequencing and compared chromatin landscapes between naïve, in vitro generated effector, exhausted (GFP-induced), and reinvigorated (KLF4-induced) CD8 T-cells.

2022-10-24 | GSE212805 | GEO

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