Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tumor-Infiltrating Myeloid Cells Confer de novo Resistance to PD-L1 Blockade through EMT-stromal and Tgf-beta Dependent Mechanisms

ABSTRACT: Most bladder cancers are poorly responsive to immune checkpoint blockade (ICB) of PD-L1. Thus, there is a need to define mechanisms of de novo resistance including contributions from tumor infiltrating immune cells. In this study, we used single-cell transcriptional profiling to map and define infiltrating myeloid cells in 10 human bladder tumors. Human data sets were qualitatively compared with myeloid data sets from the carcinogen (BBN) induced mouse model of bladder cancer which we have demonstrated to be poorly responsive to PD-L1 blockade. We previously established a signature of acquired ICB resistance which we apply here to new human and murine tumor data sets that have not received prior ICB (or systemic treatment). In doing so, we reveal conservation in EMT-stromal core genes and TGF beta signaling between human and mouse myeloid cells consistent with signatures of de novo ICB resistance. Untreated BBN tumors were highly infiltrated with M0-M2 macrophages, low in T-NK infiltration and modeled a patient subpopulation with poor survival outcome. Concordantly, the combined targeting of TGFb + PD-L1 reverted immune cell exclusion and resulted in increased survival and delayed BBN mouse tumor progression. These data constitute the stromal and myeloid cell populations as providing a coordinate mechanism de novo resistance to PD-L1 blockade in a TGF-beta dependent manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211388 | GEO | 2022/10/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Characterization of immune cells from an ICB responder and non-responder using scRNA-seq

Project description:There is a strong correlation between myeloid derived suppressor cells (MDSCs) and resistance to immune checkpoint blockade (ICB), but the detailed underlying this correlation are largely unknown. Using single-cell RNA-seq analysis in a bilateral tumor model, we found that immunosuppressive myeloid cells with characteristics of fatty acid oxidative metabolism dominate the immune-cell landscape in ICB-resistant subjects. In addition, we uncovered a previously underappreciated role of a serine/threonine kinase, PIM1, in regulating lipid oxidative metabolism via PPARγ-mediated activities. Enforced PPARγ expression sufficiently rescued metabolic and functional defects of Pim1-/- MDSCs. Consistent with this, pharmacological inhibition of PIM kinase by AZD1208 treatment significantly disrupted myeloid cell–mediated immunosuppression microenvironment and unleashed CD8+ T cell–mediated antitumor immunity, which enhanced PD-L1 blockade in preclinical cancer models. PIM kinase inhibition also sensitized non-responders to PD-L1 blockade by selectively targeting suppressive myeloid cells. Overall, we have identified PIM1 as a metabolic modulator in MDSCs that is associated with ICB resistance and can be therapeutically targeted to overcome ICB resistance.

2021-02-08 | GSE166309 | GEO

Bulk RNA sequencing of WT and Pim1 -/- bone-marrow-derived myeloid-derived suppressor cells

2021-02-08 | GSE166308 | GEO

Nuclear compartmentalization of PD-L1 suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance via histone macroH2A1 phosphorylation

Project description:Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more significantly in immunocompetent mice. p-AMPKα facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK-STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which may result from nPD-L1-increased MHC-I expression and sensitivity of tumor cells to IFN-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.

2024-11-20 | GSE276400 | GEO

CXCL9/10-engineered dendritic cells promote T cell activation and enhances immune checkpoint blockade for lung cancer.

Project description:Immune checkpoint blockade (ICB), notably Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) inhibition, has revolutionized the treatment of non-small cell lung cancer (NSCLC). However, durable responses are only observed in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment can lead to deficient T-cell recruitment and ICB resistance. We evaluated in situ vaccination with CXCL9 and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a novel strategy to overcome resistance to ICB using Lkb1-null murine NSCLC model. We utilized single-cell RNA-seq to evaluate alterations of immune infiltration associated with the new therapy, which combines intratumoral CXCL9/10-DC administration and PD-1 inhibition.

2023-05-22 | GSE232730 | GEO

Gene Expression profile for the characterization of PD-L1 blockade in melanoma model

Project description:Only a subset of patients responds to immune checkpoint blockade in melanoma. A preclinical model recapitulating the clinical activity of ICB would provide a valuable platform for mechanistic studies. We used melanoma tumors arising from an Hgftg;Cdk4R24C/R24C genetically engineered mouse (GEM) model to evaluate the efficacy of an anti-mouse PD-L1 antibody similar to the anti-human PD-L1 antibodies durvalumab and atezolizumab. Consistent with clinical observations for ICB in melanoma, anti-PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice. We also observed tumor growth delay or regression followed by recurrence. For early treatment assessment, we analyzed gene expression profiles, T cell infiltration, and T cell receptor (TCR) signatures in regressing tumors compared to tumors exhibiting no response to anti-PD-L1 treatment. We found that CD8+ T cell tumor infiltration corresponded to response to treatment, and that anti-PD-L1 gene signature response indicated an increase in antigen processing and presentation, cytokine-cytokine receptor interaction, and natural killer cell-mediated cytotoxicity. TCR sequence data suggest that an anti-PD-L1-mediated melanoma regression response requires not only an expansion of the TCR repertoire that is unique to individual mice, but also tumor access to the appropriate TCRs. Thus, this melanoma model recapitulated the variable response to ICB observed in patients and exhibited biomarkers that differentiate between early response and resistance to treatment, providing a valuable platform for prediction of successful immunotherapy.

2021-04-17 | GSE172239 | GEO

Gene Expression profile for the characterization of PD-L1 blockade in melanoma model

2021-04-20 | GSE172320 | GEO

Targeting Glycomes Sensitizes Ovarian Tumors to Immune Checkpoint Blockade II

Project description:Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, homologous recombination (HR) status-dependent glycosylation has never been explored therapeutically. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe a unique enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their resistance to anti-PD-L1 by enhancing its binding with PD-1 on CD8_ T cells. In orthotopic syngeneic EOC mouse models, inhibiting branched N-glycans, using 2-Deoxy-D-glucose, sensitizes HR-proficient, but not HR-deficient EOCs, to anti-PD-L1. These findings indicate branched N-glycans as promising therapeutic targets whose inhibition sensitizes HR-proficient EOCs to ICB by overcoming immune evasion

2024-09-29 | GSE244367 | GEO

Targeting Glycomes Sensitizes Ovarian Tumors to Immune Checkpoint Blockade

2024-03-11 | GSE244012 | GEO

Preclinical model of anti-PDL1 Immune-checkpoint blockade (ICB) resistance in breast cancer associated to low antigen presentation machinery (APM)

Project description:Immune-checkpoint blockade (ICB) immunotherapy has emerged as one of the most effective therapies in oncology by unleashing anti-tumor response. However, despite the improvement in the clinical outcome of TNBC patients, most patients do not respond yet. Thus, to understand the underlying mechanisms of ICB resistance is necessary. With this purpose, we generated a preclinical immunocompetent syngeneic model of anti-PD-L1 ICB resistance. Mouse breast cancer 4TO7 cells were orthotopically implanted by MFP and at 0.5 x 0.5 cm tumor size mice were treated with anti-PD-L1 (10mg/Kg every 3 days). Though tumors initially responded, they eventually developed resistance to anti-PD-L1 treatment. Immunotherapy resistant tumor (IRT) cells and control tumor cells were isolated and validated again for anti-PDL1 resistance in vivo. RNA from isolated resistant tumor cells was obtained using Qiagen RNA extraction kit. Samples were analyzed by bioanalyzer. Poly-A sequencing was selected for library preparation, and samples were sequenced using Illumina Hi-Seq 2500 platform with 1x50 bp settings in the Centre of Genomic Regulation (CRG). Quality raw data was performed with FastQC software. Raw reads were then aligned with the STAR mapper to the Mus musculus genome and raw counts of reads per gene was additionally obtained with STAR. Differentially expression was assessed using DESeq2 version 1.30.1 package from R/Bioconductor. Among all the results, we have seen that those IRT cells have a downregulation of the antigen presentation machinery (APM) and an enrichment of stemness signatures. Overall, the results support the notion that ICB resistance emerge from low APM activity cell populations with associated stem cell-like phenotype.

2022-01-04 | GSE176580 | GEO

EPDR1 promotes PD-L1 expression and antitumor immune evasion by inhibiting TRIM21-dependent ubiquitylation if IKBKB.

Project description:While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells is poorly understood. Here, we identified EPDR1 as an important intrinsic tumor regulator of PD-L1 expression and the antitumor T-cell response that inhibits TRIM21-dependent ubiquitylation of IKBKB. Mechanistically, EPDR1 binds to TRIM21 and disrupts its interaction with IKBKB, which suppresses the ubiquitylation and autophagosome degradation of the IKBKB protein and thus enhances NF-κB-mediated transcriptional activation of PD-L1. We further confirmed through a mouse liver cancer model that EPDR1 mediates the exhaustion of CD8+ T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals an unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression, suggesting that targeting EPDR1-TRIM21 is a potential strategy for cancer immunotherapy.

2024-06-29 | GSE250169 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data