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Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade II

ABSTRACT: Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade II

PROVIDER: PRJNA673167 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12934958.fastq.gz	Fastqsanger.gz
	SRR12934959.fastq.gz	Fastqsanger.gz
	SRR12934960.fastq.gz	Fastqsanger.gz
	SRR12934961.fastq.gz	Fastqsanger.gz
	SRR12934962.fastq.gz	Fastqsanger.gz

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Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade

Project description:Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade

| PRJNA672678 | ENA

Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade

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

Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade II

2020-10-30 | GSE160400 | GEO

Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade.

Project description:Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.

| S-EPMC7810472 | biostudies-literature

Checkpoint blockade immunotherapy induces dynamic changes in PD-1-CD8+ tumor-infiltrating T cells

Project description:An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1? TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy.

2019-01-16 | GSE122969 | GEO

Cytocidal Macrophages Cause Acute Diabetes following Checkpoint Blockade of PD-1 in NOD Mice

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

Checkpoint blockade immunotherapy induces dynamic changes in PD-1-CD8+ tumor-infiltrating T cells

Project description:Checkpoint blockade immunotherapy induces dynamic changes in PD-1-CD8+ tumor-infiltrating T cells

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Bulk RNA-seq validation experiments for \High dimensional single cell analysis predicts response to anti-PD-1 immunotherapy\

Project description:Immune checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) is effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable response. Therefore, predictive biomarkers of clinical response are urgently needed. Here, we employed high-dimensional single cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of metastatic melanoma patients before and after anti-PD-1 immunotherapy. During therapy, we observed a clear treatment response to immunotherapy in the T cell compartment. However, prior to commending therapy a strong predictor of progression free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14+CD16-HLA-DRhi monocytes. We could confirm this by conventional flow cytometry in an independent validation cohort and propose this as a novel predictive biomarker for therapy decisions in the clinic. In order to determine whether there are cell intrinsic changes in the monocyte signature, we performed RNA sequencing on sorted CD14+CD16-HLA-DRhi cells from HD, NR and R at baseline. Representative samples (n=4, each) of responders/non responders/ and healthy donors were selected from archival samples stored in the dermatology biobank according to the same clinical criteria used in the discovery and validation cohorts for CyTOF and FACS analysis. CD14+CD16-HLA-DRhiLin- (CD3, CD4, CD19, CD45RO) monocytes were sorted from frozen PBMC form blood samples from HD, R and NR at baseline.

2017-12-20 | E-MTAB-6214 | biostudies-arrayexpress

TREM2 blockade modifies the tumor myeloid landscape enhancing anti-PD-1 immunotherapy

Project description:TREM2 blockade modifies the tumor myeloid landscape enhancing anti-PD-1 immunotherapy

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PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal flu vaccine

Project description:Anti-PD-1 (aPD1) immunotherapy likely affects other immune cells including follicular helper CD4 T cells (Tfh) involved in germinal center (GC) responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on non-cancer immune responses in humans. To investigate this question, we examined the impact of aPD1 immunotherapy for cancer on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving aPD1 had more robust circulating Tfh (cTfh) responses than adults not receiving immunotherapy, and cTfh responses correlated with plasmablasts. PD-1 pathway blockade also resulted in transcriptional signatures of increased cellular proliferation in cTfh and responding B cells compared to controls.

2022-06-01 | GSE179487 | GEO

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