Open AccessMicroRNA-200a induces immunosuppression by promoting PTEN-mediated PD-L1 upregulation in osteosarcoma
Author(s) -
Zhuochao Liu,
Junxiang Wen,
Chuanlong Wu,
Chuanzhen Hu,
Jun Wang,
Qiyuan Bao,
Hongyi Wang,
Jizhuang Wang,
Qi Zhou,
Wei Li,
Yuhui Shen,
Weibin Zhang
Publication year - 2020
Publication title -
aging
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.473
H-Index - 90
ISSN - 1945-4589
DOI - 10.18632/aging.102679
Subject(s) - pten , downregulation and upregulation , immunosuppression , osteosarcoma , microrna , cancer research , medicine , biology , apoptosis , immunology , pi3k/akt/mtor pathway , gene , genetics
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.