Post-Radiotherapy GSCs EGR1-Induced GAL3 Upregulation and T Cell Exhaustion in GBM
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ABSTRACT:
PROVIDER: PRJNA1251537 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33156513.fastq.gz | Fastqsanger.gz | |||
| SRR33156514.fastq.gz | Fastqsanger.gz | |||
| SRR33156515.fastq.gz | Fastqsanger.gz | |||
| SRR33156516.fastq.gz | Fastqsanger.gz | |||
| SRR33156517.fastq.gz | Fastqsanger.gz |
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Project description:Background: Glioblastoma (GBM), a highly aggressive brain cancer, inevitably recurs due to therapy-resistant glioblastoma stem cells (GSCs). Lymphocyte activation gene 3 (LAG3) contributes to T cell exhaustion, a key immune escape mechanism. Here, we investigate that the more exhausted state of GBM-infiltrating T cells after recurrence is associated with the LAG3 and its ligand galectin 3 (GAL3). Methods: The analysis of Single-cell RNA sequencing to characterize the landscape of immune cells in newly diagnosed GBMs and recurrent GBMs respectively. Post-radiotherapy GAL3 in GSCs upregulation was validated via cell biology experiments. In vitro/in vivo loss-of-function assays assessed GAL3's impact on CD4+/CD8+ T cell cytotoxicity against GSCs. Chromatin immunoprecipitation quantitative real-time PCR was leveraged to map the regulation of GAL3 after radiotherapy in GSCs. Results: The phenomenon that recurrent glioma patients had their T cells in a more exhausted state compared to primary glioma patients, is associated with the expression of LAG3. Elevated EGR1 in post-radiotherapy GSCs upregulates LAG3 ligand GAL3 expression in GSCs, impairing CD4+/CD8+ T-cell cytotoxicity. Small molecule inhibitors targeting EGR1 in combination with anti-LAG3 monoclonal antibody suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Conclusions: GAL3 in GSCs plays critical roles in maintaining the exhaustion stage of T cells and inhibits cytotoxic capacity of CD4+/CD8+ T cells, highlighting an interplay between GSCs and GBM-infiltrating T cells. Small molecule inhibitors in combination with anti-LAG3 monoclonal antibody may effectively improve GBM treatment.
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Project description:SUMMARY Terminal differentiation has been proposed as a therapeutic strategy for glioblastoma (GBM). Culturing of GBM derived tumor initiating glioma stem cells (GSCs) in fetal bovine serum containing media is a proposed mode of differentiation that is thought to induce loss of stem cell characteristics, promote neural lineage differentiation and a parallel loss of tumor initiation capacity. Here we show that GSCs retained both neurosphere formation and tumor initiation abilities after short or long term serum exposure. Under serum induced differentiating conditions, GSCs expressed both neural lineage and stem cell markers, highlighting the aberrant pseudo-differentiation state. GSCs maintained under adherent differentiating conditions continued to proliferate and initiate tumor formation with efficiencies similar to GSCs maintained under proliferating (neurosphere) conditions. Proneural (PN) GSCs under serum exposure showed an induction of mesenchymal (MES) gene expression signatures. Our data indicate that the tumor initiation ability of GSCs is independent of their differentiation state and that terminal differentiation as a therapeutic approach may not effectively negate tumorigenicity of GSCs. SIGNIFICANCE Terminal differentiation has been proposed as a therapeutic strategy for glioblastoma (GBM). Culturing of GBM derived tumor initiating glioma stem cells (GSCs) in fetal bovine serum containing media is a proposed mode of differentiation that is thought to induce loss of stem cell characteristics, promote neural lineage differentiation and a parallel loss of tumor initiation capacity. Here we show that GSCs retained both neurosphere formation and tumor initiation abilities after short or long term serum exposure. Under serum induced differentiating conditions, GSCs expressed both neural lineage and stem cell markers, highlighting the aberrant pseudo-differentiation state. GSCs maintained under adherent differentiating conditions continued to proliferate and initiate tumor formation with efficiencies similar to GSCs maintained under proliferating (neurosphere) conditions. Proneural (PN) GSCs under serum exposure showed an induction of mesenchymal (MES) gene expression signatures. Our data indicate that the tumor initiation ability of GSCs is independent of their differentiation state and that terminal differentiation as a therapeutic approach may not effectively negate tumorigenicity of GSCs.
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Project description:We demonstrate that the catalytic subunit of Polycomb Repressive Complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which in turn promotes resistance to radiation in GSCs. Clinically, EZH2 and MELK are co-expressed in GBM and significantly induced in post-irradiation recurrent tumors whose expression inversely correlated with patient prognosis. Through gain-and loss-of-function study, our data show that MELK or FOXM1 contributes on GSC radioresistance by regulation of EZH2. We used microarrays to validate EZH2 target gene expression. GSCs were treated with shNT (control), shMELK, shFOXM1, and EZH2 overexpression. Total RNA was isolated using the Qiagen RNeasy kit (Qiagen).
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