Clonal replacement of tumor-specific T cells following PD-1 blockade [bulk RNA]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA509911 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8315790_1.fastq.gz | Fastqsanger.gz | |||
| SRR8315790_2.fastq.gz | Fastqsanger.gz | |||
| SRR8315800_1.fastq.gz | Fastqsanger.gz | |||
| SRR8315800_2.fastq.gz | Fastqsanger.gz | |||
| SRR8315810_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, the clonal origin of tumor-specific T cells following checkpoint blockade in patients remains unclear. Here, we performed paired single-cell RNA- and T cell receptor (TCR)- sequencing on site-matched tumors from patients with basal cell carcinoma (BCC) pre- and post-anti-PD-1 therapy. Tracking TCR clonotypes and transcriptome phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the response to treatment was accompanied by a clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this response was not accompanied by an expansion of pre-existing tumor-specific T cell clonotypes; rather, expanded T cell clones post-therapy comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in tumor-specific exhausted CD8+ T cells, compared to other distinct T cell phenotypes, and was more evident in patients who exhibited a clinical response to treatment. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that the chronic activation of pre-existing tumor-infiltrating T cells may limit their re-invigoration following checkpoint blockade, and that a successful response relies on the expansion of a distinct repertoire of tumor-specific T cell clones.
2019-05-24 | GSE123812 | GEO
Project description:Clonal replacement of tumor-specific T cells following PD-1 blockade
| PRJNA509907 | ENA
Project description:Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, the clonal origin of tumor-specific T cells following checkpoint blockade in patients remains unclear. Here, we performed paired single-cell RNA- and T cell receptor (TCR)- sequencing on site-matched tumors from patients with basal cell carcinoma (BCC) pre- and post-anti-PD-1 therapy. Tracking TCR clonotypes and transcriptome phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the response to treatment was accompanied by a clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this response was not accompanied by an expansion of pre-existing tumor-specific T cell clonotypes; rather, expanded T cell clones post-therapy comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in tumor-specific exhausted CD8+ T cells, compared to other distinct T cell phenotypes, and was more evident in patients who exhibited a clinical response to treatment. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that the chronic activation of pre-existing tumor-infiltrating T cells may limit their re-invigoration following checkpoint blockade, and that a successful response relies on the expansion of a distinct repertoire of tumor-specific T cell clones.
2019-05-24 | GSE123813 | GEO
Project description:Clonal replacement of tumor-specific T cells following PD-1 blockade [single cells]
| PRJNA509910 | ENA
Project description:Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2-4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.
| S-EPMC6689255 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-05-24 | GSE123814 | GEO
Project description:We report results of transcriptional profiling of ex vivo MC38 murine organotypic tumor spheroids following programmed death-1 (PD-1) blockade compared to isotype control IgG treatment by bulk and single-cell RNA-sequencing after 6 days of treatment. Additionally, we report results from single-cell RNA-sequencing of MC38 tumors treated in vivo with PD-1 blockade versus isotype control IgG to validate ex vivo workflow.
2020-10-28 | GSE160228 | GEO
Project description:Blocking the action of the PD-1 protein in lymphocytes results in their activation leading to an effective immune response in cancers and in experimental viral infections. But such immunotherapy in clinical cases results in immune adverse effects among them the development of autoimmune diabetes. In the diabetes susceptible NOD mice, blockade of the PD-L1/PD-1 pathway during the pre-diabetic stage results in severe and acute diabetes. Single-cell RNA sequencing and flow cytometry analysis of islets following blockade of the PD-L1/PD-1 pathway identified a cascade of cellular interactions involving resident macrophages and diabetogenic T cells. Such reactions led to the recruitment of monocyte derived macrophages that caused diabetes. Elimination of the monocyte derived macrophages resulted in protection. The cytocidal activity was highly dependent on IFNγ signaling and the downstream release of nitric oxide by the monocyte derived macrophages. The activation of macrophages required both the participation of CD4 and CD8 T cells. Our studies call attention to macrophages as the major effector cell following blockade of PD-1. Targeting the monocyte-derived macrophage provides a new option to prevent and treat immune checkpoint blockade induced diabetes and perhaps other immune adverse reactions.
2020-11-12 | GSE150178 | GEO
Project description:While T cell accumulation in tumors is associated with response to immune checkpoint blockade (ICB), many T cell-rich tumors fail to respond to ICB. Here we leveraged a large neoadjuvant PD-1 blockade trial in hepatocellular carcinoma (HCC) to search for correlates of ICB response within T cell-rich tumors. Paired scRNAseq/TCRseq of nearly one million immune cells revealed that tumor responses to ICB correlated with significant clonal expansion of intratumoral CH25H+CXCL13+IL-21+CD4 T cells and GranzymeK+PD-1+CD8 effector T cells, whereas terminally exhausted CD39hiToxhiPD-1hi CD8 clones dominated in non-responders. Notably, proliferating and progenitor CD8 T cells clones were found in tumors of responders and non-responders. However, tumors from responders were highly enriched in mregDCs, a DC state triggered by capture of tumor debris, which formed physically interacting cellular triads with Tfh-like CD4 and progenitor-like CD8 T cells. Receptor-ligand analysis revealed unique interactions within these triads that may promote progenitor CD8 T cell differentiation into effector cells upon PD-1 blockade. These results suggest that discrete cellular niches that include mregDCs and Tfh-like CD4 T cells might control the differentiation of tumor-specific progenitor CD8 T cell clones into effective anti-tumor T cells in human tumors.
2023-06-16 | GSE206325 | GEO
Project description:We report results of transcriptional profiling of ex vivo MC38 murine organotypic tumor spheroids following programmed death-1 (PD-1) blockade compared to isotype control IgG treatment by bulk and single-cell RNA-sequencing after 6 days of treatment. Additionally, we report results from single-cell RNA-sequencing of MC38 tumors treated in vivo with PD-1 blockade versus isotype control IgG to validate ex vivo workflow.
2020-10-30 | GSE160400 | GEO