The Role of PD-1/PD-L1 in Overshooting Osteoclastogenesis in Periprosthetic Joint Infections
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1252699 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33212063.fastq.gz | Fastqsanger.gz | |||
| SRR33212064.fastq.gz | Fastqsanger.gz | |||
| SRR33212065.fastq.gz | Fastqsanger.gz | |||
| SRR33212066.fastq.gz | Fastqsanger.gz | |||
| SRR33212067.fastq.gz | Fastqsanger.gz |
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Project description:Periprosthetic joint infection (PJI) is a critical complication following arthroplasty, leading to increased prosthesis failure rates post-treatment. This study explores the role of PD-1/PD-L1 signaling in osteoclastogenesis associated with PJI. Peripheral blood, bone, and bone marrow of 65 patients (20 primary osteoarthritis, 21 PJI septic explantation, 24 PJI prosthesis reimplantation) were analyzed for their bone microstructure and cell composition. Immunocytochemistry, RT-qPCR, flow cytometry, bone resorption assay, ELISA, and RNA sequencing were performed to investigate the effects of PD-1 stimulation and blockade on osteoclast formation. PD-1 positive monocytes and sPD-L1 levels were elevated in PJI. Stimulation with PD-L1 enhanced osteoclastogenesis, while PD-1 inhibitor nivolumab reversed these effects. Impact of PD-1 and nivolumab was significantly more pronounced in PJI compared to the control. Our study suggests PD-1/PD-L1 signaling plays a significant role in PJI-related osteoclastogenesis. These findings highlight the potential of PD-1 inhibitors as a novel approach to manage this challenging clinical condition.
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Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.
2015-05-01 | E-GEOD-65041 | biostudies-arrayexpress
Project description:Sample description: Anti-PD-L1 co-immunoprecipitation samples from cultured wild-type, PD-L1-VavCre or PD-L1-LysMCre bone marrow cells.
Samples are: KO-VavCre-1 (775112) v.s. WT-1 (775113); KO-LysMCre-2 (775114) v.s. WT-2 (775115). Among these samples, KO-VavCre-1 and KO-LysMCre-2 are the respective blank controls (from knockout mice).
Three 10-cm plates of bone marrow cells from each genotype (wild-type or PD-L1-VavCre, and wild-type or PD-L1-LysMCre) of 2-month-old male littermate mice at a density of 2.8 * 107 cells/plate were cultured in the presence of 40 ng/mL of mouse M-CSF for 3 days. Cells were washed with PBS and resuspend in lysis buffer (50 mM Tris pH 7.5, 150 mM NaCl, 1% NP-40, 1 mM PMSF, 1x protease inhibitor cocktail) for 4 hours at 4C. The lysate was centrifuged at 12,000 g for 10 min. The supernatant was mixed with 2 micro G of anti-PD-L1 antibody and incubated for overnight at 4C. Protein A/G agarose (Santa Cruz) was added and incubated for 2 hours at 4C. Agarose was washed with lysis buffer for four times. The samples were separated in SDS-PAGE gel (10-mm length per lane). Coomassie blue stained gel slices were analyzed by mass spectrometry.
Samples were digested overnight with trypsin (Pierce) following reduction and alkylation with DTT and iodoacetamide (Sigma-Aldrich). The samples then underwent solid-phase extraction cleanup with an Oasis HLB plate (Waters) and were subsequently dried and reconstituted into 10 microL of 2% ACN, 0.1% TFA. 2 microL of these samples were injected onto a QExactive HF mass spectrometer coupled to an Ultimate 3000 RSLC-Nano liquid chromatography system. Samples were injected onto a 75 micro M i.d., 15-cm long EasySpray column (Thermo) and eluted with a gradient from 0-28% buffer B over 90 min with a flow rate of 250 nL/min. Buffer A contained 2% (v/v) ACN and 0.1% formic acid in water, and buffer B contained 80% (v/v) ACN, 10% (v/v) trifluoroethanol, and 0.1% formic acid in water. The mass spectrometer operated in positive ion mode with a source voltage of 2.2 kV and an ion transfer tube temperature of 275 C. MS scans were acquired at 120,000 resolution in the Orbitrap and up to 20 MS/MS spectra were obtained for each full spectrum acquired using higher-energy collisional dissociation (HCD) for ions with charges 2-8. Dynamic exclusion was set for 20 second after an ion was selected for fragmentation.
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Project description:PD-L1 Inhibitor Regulates the miR-33a-5p/PTEN Signaling Pathway and Can Be Targeted to Sensitize Glioblastomas to Radiation. Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Ionizing radiation (IR) is a standard treatment for GBM patients and results in DNA damage. However, the clinical efficacy of IR is limited due to therapeutic resistance. The programmed death ligand 1 (PD-L1) blockade has a shown the potential to increase the efficacy of radiotherapy by inhibiting DNA damage and repair responses. The miR-33a-5p is an essential microRNA that promotes GBM growth and self-renewal. In this study, we investigated whether a PD-L1 inhibitor (a small molecule inhibitor) exerted radio-sensitive effects to impart an anti-tumor function in GBM cells by modulating miR-33a-5p. U87 MG cells and U251 cells were pretreated with PD-L1 inhibitor. The PD-L1 inhibitor-induced radio-sensitivity in these cells was assessed by assaying cellular apoptosis, clonogenic survival assays, and migration. TargetScan and luciferase assay showed that miR-33a-5p targeted the phosphatase and tensin homolog (PTEN) 3' untranslated region. The expression level of PTEN was measured by western blotting, and was also silenced using small interfering RNAs. The levels of DNA damage following radiation was measured by the presence of γ-H2AX foci, cell cycle, and the mRNA of the DNA damage-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated that the PD-L1 inhibitor significantly decreased the expression of the target gene, miR-33a-5p. In addition, pretreatment of U87 MG and U251 cells with the PD-L1 inhibitor increased radio-sensitivity, as indicated by increased apoptosis, while decreased survival and migration of GBM cells. Mir-33a-5p overexpression or silencing PTEN in U87 MG and U251 cells significantly attenuated PD-L1 radiosensitive effect. Additionally, PD-L1 inhibitor treatment suppressed the expression of the DNA damage response-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated a novel role for the PD-L1 inhibitor in inducing radio- sensitivity in GBM cells, where inhibiting miR-33a-5p, leading to PTEN activated, and inducing DNA damage was crucial for antitumor immunotherapies to treat GBM.
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