MicroRNA-200a induces immunosuppression by promoting PTEN-mediated PD-L1 upregulation in osteosarcoma.

Zhuochao Liu,Qiyuan Bao,Li Wei,Chuanlong Wu,Weibin Zhang,Hongyi Wang,Jun Wang,Junxiang Wen,Jizhuang Wang,Yuhui Shen,Qi Zhou,Chuanzhen Hu

doi:10.18632/aging.102679

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.

Highlights

Osteosarcoma is the most common primary malignancy of bones in children and adolescents [1]
These results suggest that miR-200a regulates PD-L1expression in doxorubicin-treated osteosarcoma cells
We further examined the proportions of CD4+ T cells, CD8+ T cells, Foxp3+ regulatory T lymphocytes (Tregs), and IFN-γ+ cytotoxic T lymphocytes (CTLs) in the www.aging-us.com www.aging-us.com www.aging-us.com different groups of tumor tissues to determine the effects of miR-200a on anti-tumor immunity in vivo

Summary

Introduction

Osteosarcoma is the most common primary malignancy of bones in children and adolescents [1]. In the 1970s, the application of chemotherapy substantially improved the 5-year survival rate of osteosarcoma patients [2]. Due to immunosuppression induced by chemotherapeutic agents such as cisplatin and doxorubicin, as well as the lack of new chemotherapeutic drugs owing to the heterogeneity of osteosarcoma, there has been no significant improvement in the 5-year survival rate since . Newer therapeutic strategies are needed to improve survival rates of osteosarcoma patients. Our previous study suggested that doxorubicin treatment would cause immunosuppression by inducing PD-L1 expression [3]. The high expression of PD-L1 predicts a poorer 5-year event-free-survival of osteosarcoma patients [4] and is correlated with early metastasis [5]

Methods

Results

Conclusion