Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Clonal deletion of tumor-specific T cells by IFN-g confers therapeutic resistance to combination immune checkpoint blockade

ABSTRACT: Clonal deletion of tumor-specific T cells by IFN-g confers therapeutic resistance to combination immune checkpoint blockade

PROVIDER: PRJNA498104 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR8098510.fastq.gz	Fastqsanger.gz
	SRR8098501.fastq.gz	Fastqsanger.gz
	SRR8098511.fastq.gz	Fastqsanger.gz
	SRR8098502.fastq.gz	Fastqsanger.gz
	SRR8098512.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 12

Similar Datasets

Clonal deletion of tumor-specific T cells by IFN-g confers therapeutic resistance to combination immune checkpoint blockade

Project description:Combination immunotherapy is being developed with the goal of enhancing anti-tumor immunity. Despite remarkable clinical responses, most patients do not experience complete responses from combination checkpoint blockade treatments. Therefore, a need exists to further explore the mechanisms of resistance to these therapies. Here, we investigate whether tumor burden could be an important factor in determining the treatment outcomes of combination checkpoint blockade. We found that while combined anti-CTLA-4 and anti-PD-1 improves control of established tumors, this combination can paradoxically compromise anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. This paradoxical outcome results from treatment-induced deletion of tumor-specific T cells that is mediated through IFN-γ. Activated tumor-specific T cells express higher levels of IFN-γ receptor and are more susceptible to apoptosis. As a result, combination treatment alters the T cell repertoire landscape, skewing the distribution of T cells toward lower frequency clonotypes. Deficiency of the IFN-γ receptor on immune cells restores anti-tumor activity. Additionally, tumor-specific T cells lacking the IFN-γ receptor demonstrate a significant survival advantage compared to their wild-type counterparts in tumor-bearing mice receiving combination therapy. Finally, we show that combination therapy induces significantly higher levels of IFN-γ in the low versus high tumor burden state on a per cell basis, reflecting their less exhausted immune status. This elevated IFN-γ secretion in the LTB state therefore contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade. Our report underscores the importance of achieving the optimal magnitude of immune stimulation for successful immunotherapy strategies.

2018-10-24 | GSE121694 | GEO

Early Changes In B Cell Subsets Predict Risk Of Autoimmunity Following Combination Immune Checkpoint Blockade

Project description:We report changes in B cells in patients treated with combination immune checkpoint blockade (CCB; anti-CTLA4 and anti-PD1)

2017-11-29 | GSE104600 | GEO

Immunotherapy study of phagocytosis checkpoint blockade in combination with radiotherapy

Project description:Immunotherapy study of phagocytosis checkpoint blockade in combination with radiotherapy

| PRJNA812010 | ENA

Clonal Deletion of Tumor-Specific T Cells by Interferon-? Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade.

Project description:Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-? (IFN-?) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-? production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-? secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.

| S-EPMC6886475 | biostudies-literature

hMENA isoforms regulate cancer intrinsic Type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC [RNA-seq]

Project description:Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the IFN pathway that may be detrimental rather than beneficial. Effects of hMENA11a down-regulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes.

2023-08-30 | GSE224216 | GEO

hMENA isoforms regulate cancer intrinsic Type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC [ATAC-seq]

2023-08-30 | GSE224246 | GEO

Tumour mtDNA mutations drive aerobic glycolysis to enhance checkpoint blockade

Project description:Mitochondrial DNA (mtDNA) encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutations in the cancer genome, with truncating mutations in complex I genes being over-represented1 . While mtDNA mutations have been associated with both improved and worsened prognoses in several cancer lineages1–3, whether these mutations are drivers, or exert any functional effect on tumour biology remains controversial. Here we discover that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment of mouse and human cancer in a mutation load-dependent fashion, encouraging an anti-tumour immune response. This subsequently sensitises both mouse and human cancers with high mtDNA mutant heteroplasmy to immune checkpoint blockade. Strikingly, patient lesions bearing >50% mtDNA mutation load demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.

2023-11-08 | PXD039705 | Pride

Gut microbiome sequencing in patients receiving combination immune checkpoint blockade

Project description:This dataset contains 16S and WMS data for gut (fecal) microbiome samples taken from patients treated with combined anti-CTLA-4 and anti-PD-1 checkpoint blockade for advanced melanoma.

| EGAS00001004885 | EGA

Tumour mtDNA mutations drive aerobic glycolysis to enhance checkpoint blockade (part 2)

2023-11-08 | PXD044987 | Pride

Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

Project description:Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

| PRJNA397812 | ENA