Research Paper Volume 12, Issue 2 pp 1213—1236

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

Zhuochao Liu 1, 2, *, , Junxiang Wen 1, 2, *, , Chuanlong Wu 1, , Chuanzhen Hu 3, , Jun Wang 2, , Qiyuan Bao 1, , Hongyi Wang 1, , Jizhuang Wang 1, , Qi Zhou 2, , Li Wei 2, , Yuhui Shen 1, 2, , Weibin Zhang 1, 2, ,

  • 1 Department of Orthopaedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
  • 2 Shanghai Institute of Orthopedics and Traumatology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
  • 3 Department of Orthopaedics, Shanghai Tenth People’s Hospital, Tongji University, Shanghai 200072, China
* Equal contribution

received: October 3, 2019 ; accepted: December 25, 2019 ; published: January 24, 2020 ;

https://doi.org/10.18632/aging.102679
How to Cite

Copyright © 2020 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

PD-L1: programmed death-ligand 1; PTEN: phosphatase and tensin homolog deleted on chromosome ten; T-regs: regulatory T lymphocytes; CTLs: cytotoxic T lymphocytes; HNSCC: head and neck squamous cell carcinoma; miRNA: microRNA; OE: overexpression; EMT: epithelial-mesenchymal transition; MET: mesenchymal-epithelial transition; PBS: phosphate buffered saline; qRT-PCR: quantitative reverse transcription-polymerase chain reaction; CCK-8: cell counting kit-8; MDR: multidrug resistance; RNA-seq: RNA sequencing; GEO: gene expression omnibus.