Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

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

ABSTRACT: The activation of PD-1 (Programmed Death receptor-1) on T cells can cause T cell exhaustion and immune tolerance. Some tumors up-regulate the expression of the ligand of PD-1, namely PD-L1 (Programmed Death Receptor-Ligand 1), thus preventing anti-tumor immune response and promoting immune-escape. Previous studies have shown that JAK2 (Janus Kinase 2) signaling can promote PD-L1 expression in Hodgkin Lymphoma. In Myeloproliferative Neoplasms (MPN), JAK2 is frequently characterized by the the presence of the point-mutation V617F, which leads to its constitutive activation and to uncontrolled cell proliferation and survival. Accordingly, tumor cell lines expressing JAK2 V617F express higher levels of PD-L1 as compared to tumor cell lines negative for such mutations. In this experiment, we transfected BaF3 cells with a vector (plasmid for Murine Stem Cell Virus) containing the gene for JAK2 with the point-mutation V617F. As control, we used BaF3 cells transfected with the same vector, but without the gene for JAK2 V617F (empty vector). Both the cell lines (with/without JAK2 V617F) were co-cultured with primary murine T cells. When co-cultured with BaF3 cells expressing JAK2 V617F, T cells upregulated genes connected to senescence pathways, showed increased apoptosis, less cytokine production, and displayed other forms of dysfunction which can be associated with the activation of PD-1.

ORGANISM(S): Mus musculus

SUBMITTER: Robert Zeiser

PROVIDER: E-MTAB-5028 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Oncogenic JAK2<sup>V617F</sup> causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms.

Prestipino Alessandro A Emhardt Alica J AJ Aumann Konrad K O'Sullivan David D Gorantla Sivahari P SP Duquesne Sandra S Melchinger Wolfgang W Braun Lukas L Vuckovic Slavica S Boerries Melanie M Busch Hauke H Halbach Sebastian S Pennisi Sandra S Poggio Teresa T Apostolova Petya P Veratti Pia P Hettich Michael M Niedermann Gabriele G Bartholomä Mark M Shoumariyeh Khalid K Jutzi Jonas S JS Wehrle Julius J Dierks Christine C Becker Heiko H Schmitt-Graeff Annette A Follo Marie M Pfeifer Dietmar D Rohr Jan J Fuchs Sebastian S Ehl Stephan S Hartl Frederike A FA Minguet Susana S Miething Cornelius C Heidel Florian H FH Heidel Florian H FH Kröger Nicolaus N Triviai Ioanna I Brummer Tilman T Finke Jürgen J Illert Anna L AL Ruggiero Eliana E Bonini Chiara C Duyster Justus J Pahl Heike L HL Lane Steven W SW Hill Geoffrey R GR Blazar Bruce R BR von Bubnoff Nikolas N Pearce Erika L EL Zeiser Robert R

Science translational medicine 20180201 429

Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2<sup>V617F</sup>-mutant ...[more]

PMID: 29467301

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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.

Dataset Information

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

Publications

Oncogenic JAK2<sup>V617F</sup> causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms.

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