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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
MicroRNA-200a induces immunosuppression by promoting PTEN-mediated PD-L1 upregulation in osteosarcoma
Zhuochao Liu1,2, Junxiang Wen1,2, Chuanlong Wu1
1Department of Orthopaedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Abstract:
In this study, we identified microRNAs that regulate the expression of programmed death-ligand 1(PD-L1) in osteosarcoma and investigated their role in PD-L1-targeted immunotherapy. MicroRNA sequencing analysis showed that the expression of PD-L1 is regulated by microRNA-200a in U2OS, 143B, and K7 osteosarcoma cells. MicroRNA-200a overexpression induced the upregulation of PD-L1 in the osteosarcoma cells. CD8+ T cells co-cultured with microRNA-200a-overexpressing osteosarcoma cells showed reduced survival, proliferation, and secretion of granzyme B and perforin. The same phenomenon was also observed in the K7-derived syngeneic mouse model, as microRNA-200a promoted tumor growth by increasing the percentage of Foxp3+ regulatory T lymphocytes while reducing the proportions of CD4+, CD8+, and IFN-γ+ cytotoxic T lymphocytes. But microRNA-200a overexpression group was also more responsive to PD-L1-targeted immunotherapy than the controls. In addition, the tumor tissues from 32 osteosarcoma patients showed that high expression of microRNA-200a and PD-L1 was associated with poor tumor necrosis rate after chemotherapy. Moreover, we confirmed that tensin homolog deleted on chromosome ten (PTEN) could act as the target gene for microRNA-200a during the upregulation of PD-L1. Thus, our findings provide important and novel insight into a regulatory axis involving microRNA-200a/PTEN/ PD-L1 axis, which determines osteosarcoma growth and the efficacy of PD-L1-targeted immunotherapy.
Insights
MicroRNA-200a promotes osteosarcoma growth and PD-L1 expression by targeting PTEN. This axis impacts immunotherapy efficacy and patient outcomes, offering new therapeutic targets.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Osteosarcoma is a challenging bone cancer with limited treatment options.
- Programmed death-ligand 1 (PD-L1) is a key immune checkpoint in cancer immunotherapy.
- MicroRNAs play crucial roles in regulating gene expression and cellular processes.
Purpose of the Study:
- To identify microRNAs regulating PD-L1 expression in osteosarcoma.
- To investigate the role of microRNA-200a in osteosarcoma progression and PD-L1-targeted immunotherapy.
- To elucidate the regulatory mechanism of microRNA-200a on PD-L1 expression.
Main Methods:
- MicroRNA sequencing analysis in osteosarcoma cell lines (U2OS, 143B, K7).
- In vitro co-culture assays with CD8+ T cells and osteosarcoma cells.
- In vivo studies using a K7-derived syngeneic mouse model.
- Analysis of tumor tissues from osteosarcoma patients.
- Western blot and luciferase reporter assays to confirm target gene interaction.
Main Results:
- MicroRNA-200a was identified as a regulator of PD-L1 expression in osteosarcoma cells.
- MicroRNA-200a overexpression led to increased PD-L1 levels, reduced T cell function, and promoted tumor growth.
- The microRNA-200a/PTEN/PD-L1 axis was confirmed, with PTEN acting as a target gene.
- High microRNA-200a and PD-L1 expression correlated with poor post-chemotherapy tumor necrosis in patients.
- The microRNA-200a overexpression group showed enhanced response to PD-L1-targeted immunotherapy.
Conclusions:
- MicroRNA-200a promotes osteosarcoma growth and immune evasion by upregulating PD-L1 via the PTEN pathway.
- The microRNA-200a/PTEN/PD-L1 axis is a critical determinant of osteosarcoma progression and immunotherapy response.
- Targeting this axis holds potential for improving osteosarcoma treatment strategies.
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