Dataset Information

Kosinsky2018 - Radiation and PD-(L)1 treatment combinations

ABSTRACT: This is a quantitative systems pharmacology (QSP) model that describes key elements of the cancer immunity cycle and the tumor microenvironment, tumor growth, as well as dose-exposure-target modulation features. The model describes the synergistic kinetic effects underlying immune cell interactions as linked to tumor size modulation under immunotherapeutic and radiological treatments.

ORGANISM(S): Mus musculus

SUBMITTER: Lucian Smith

PROVIDER: MODEL1911140003 | biostudies-other |

SECONDARY ACCESSION(S): 29486799

REPOSITORIES: biostudies-other

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Publications

Radiation and PD-(L)1 treatment combinations: immune response and dose optimization via a predictive systems model.

Kosinsky Yuri Y Dovedi Simon J SJ Peskov Kirill K Voronova Veronika V Chu Lulu L Tomkinson Helen H Al-Huniti Nidal N Stanski Donald R DR Helmlinger Gabriel G

Journal for immunotherapy of cancer 20180227 1

<h4>Background</h4>Numerous oncology combination therapies involving modulators of the cancer immune cycle are being developed, yet quantitative simulation models predictive of outcome are lacking. We here present a model-based analysis of tumor size dynamics and immune markers, which integrates experimental data from multiple studies and provides a validated simulation framework predictive of biomarkers and anti-tumor response rates, for untested dosing sequences and schedules of combined radia ...[more]

PMID: 29486799

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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

Kosinsky2018 - Radiation and PD-(L)1 treatment combinations

Publications

Radiation and PD-(L)1 treatment combinations: immune response and dose optimization via a predictive systems model.

Similar Datasets

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