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Bulk RNAseq of anti-PD1-induced cardiac dysfunction in C57BL/6J mice

ABSTRACT: C57BL6/J mice were treated with anti-PD-1 for 2 or 4 weeks, or with isotype control antibody. In echocardiography, cardiac dysfunction was seen both after 2 and 4 weeks, with decreased ejection fraction and left ventricular dilation. Bulk RNA sequencing of the hearts after treatment was performed to identify the mechanisms of anti-PD-1-induced cardiac dysfunction.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mus musculus

SUBMITTER: Tamás Gergely

PROVIDER: E-MTAB-12388 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment.

Gergely Tamás G TG Kucsera Dániel D Tóth Viktória E VE Kovács Tamás T Sayour Nabil V NV Drobni Zsófia D ZD Ruppert Mihály M Petrovich Balázs B Ágg Bence B Onódi Zsófia Z Fekete Nóra N Pállinger Éva É Buzás Edit I EI Yousif Laura I LI Meijers Wouter C WC Radovits Tamás T Merkely Béla B Ferdinandy Péter P Varga Zoltán V ZV

British journal of pharmacology 20221213 6

<h4>Background and purpose</h4>Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T-cells against tumours. However, enhanced T-cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI-induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD-1 inhibition on cardiac function and explore the molecular mechanisms of ICI-induced car ...[more]

PMID: 36356191

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Evading immune evasion via reprograming of the tumor microenvironment by radiotherapy and simultaneous targeting of TGF-β/PD-L1

Project description:Single cell transcriptome showed TGF-β expression is confined to PD-L1+ endothelium and M2 /lipofibroblast-like cells. Hence, superior effects of BA could be attributed to its ability to trap TGF-β to relevant PD-L1+ compartments. Mice were irradiated (photon) and one group of mice was treated with Bintrafusp. Lungs were subsequently dissociated and processed with the 10x genomics 3 prime v2 kit.

2021-08-10 | E-MTAB-10633 | biostudies-arrayexpress

Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. Mouse tumour samples

Project description:While immune checkpoint blockade therapy (ICBT) benefits cancer patients, many fail to maintain their response due to adaptive resistance mechanisms. IFNγ is critical for cellular immunity, but also promotes adaptive resistance to ICBT. We have established a role for PARP14 in mediating IFNγ-induced adaptive resistance. We confirm that chronic pre-treatment of tumour cells with IFNγ confers resistance to α-PD-1 antibodies in syngeneic mouse tumour models. We identified that PARP14 was consistently upregulated in cancer cells treated chronically with IFNγ as well as in IFNγ-high melanoma samples. Further, we showed that PARP14 knockdown or pharmacological inhibition restores sensitivity to α-PD-1 antibodies accompanied by increased immune cell infiltration into tumours but the decreased presence of regulatory T cells. RNA sequencing analysis of tumours and cultured cells treated with PARP14 inhibitor showed an upregulation of inflammatory-related pathways. In conclusion, PARP14 is an actionable target for reversing IFNγ-driven adaptive resistance to ICBT.

2023-08-08 | E-MTAB-12194 | biostudies-arrayexpress

Single-cell RNA-sequencing of immune cells in (1) mouse Renca model treated with anti-CSF1R and (2) mouse MC38 model treated with anti-CD40

Project description:Single-cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application towards dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune cells in mouse tumors and identified specific macrophage and conventional dendritic cell (cDC) subsets that are comparable to previously described human myeloid populations. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R selectively depleted macrophages with an inflammatory signature but spared a macrophage population that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated of a cDC1-Ccl22 population and gradually increased Bhlhe40+ Th1-like cells and CD8+ memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing. Raw FASTQ sequences have been uploaded to European Nucleotide Archive (Study #: PRJEB34105 (ERP116961))

2020-02-23 | E-MTAB-8832 | biostudies-arrayexpress

RNAseq of tumor samples from CT26 syngeneic mouse treated with a PD-L1 and CTLA-4 immunotherapy combination

Project description:The ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as PD-1, PD-L1, and CTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging. Utilizing RNAseq transcriptomic profiling, we have characterised the changes in gene regulatory pathways and immune populations in CT26 mice after treatment with the combination of anti-PD-L1 and anti-CTLA-4 antibodies. At day 7 post tumor implant, the pathways analysis of differentially expressed genes indicated an enrichment for migration of leukocytes in response to inflammation and communication between innate and adaptive immune cells. Similarly, analysis of upstream regulators suggested that lipopolysaccharide, IL-1B, TNF, IFNG, and NFKB1A pathways associated with inflammation were activated. At day 14, pathways related T-helper cell signalling pathways were upregulated. In addition, upstream regulators of the lipopolysaccharide and IFNG pathway, as well STAT1 and IL21 pathway were enriched, indicative of innate and adaptive immune response to inflammation.

2020-04-16 | E-MTAB-7777 | biostudies-arrayexpress

Analysis of mouse T cell transcription profile after co-culture with BaF3 cells with or without the oncogenic point mutation JAK2 V617F

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2018-12-01 | E-MTAB-5028 | biostudies-arrayexpress

scRNAseq of CD45+ FACS sorted cells from 5555_V600-BRAFmut mouse melanoma tumours treated with Ranolazine and anti-PD

Project description:Single cell RNAseq libraries generation of the sub-population of the immune infiltrate of 5555_V600-BRAFmut mouse melanoma tumours. The selected populations have been isolated by using CD45-APC labelling and FACS-sorted isolated. Tumours were treated with Ranolazine (an FAO inhibitor) and anti-PD-L1 (an immunotherapeutic agent blocking the checkpoint inhibitor PD-L1 molecule). At the desired time point tumours were collected and processed as described in the procedure sections. Then FACS was performed and single cell solution was applied to the 10X library preparation kit pipeline.

2023-06-28 | E-MTAB-12315 | biostudies-arrayexpress

Single-cell sequencing of tissue-resident CD4+ T cells that drive compartmentalized immunopathology in the CNS

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2022-02-19 | E-MTAB-11422 | biostudies-arrayexpress

Single-cell sequencing of tissue-resident CD8+ T cells that drive compartmentalized immunopathology in the CNS

2022-03-14 | E-MTAB-11511 | biostudies-arrayexpress

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2012-10-16 | E-GEOD-40514 | biostudies-arrayexpress

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