Long noncoding RNA Pvt1 regulates the immunosuppression activity of granulocytic myeloid-derived suppressor cells in tumor-bearing mice

Yu Zheng,Ping Xu,Xueli Xia,Jie Ma,Shengjun Wang,Xinyu Tian,Fenghua Cao,Tingting Wang,Jie Tian,Huaxi Xu

doi:10.1186/s12943-019-0978-2

Abstract

BackgroundMyeloid-derived suppressor cells (MDSCs) participate in tumor-elicited immunosuppression by dramatically blocking T-cell-induced antitumor responses, thereby influencing the effectiveness of cancer immunotherapies. Treatments that alter the differentiation and function of MDSCs can partially restore antitumor immune responses. The long noncoding RNA plasmacytoma variant translocation 1 (lncRNA Pvt1) is a potential oncogene in a variety of cancer types. However, whether lncRNA Pvt1 is involved in the regulation of MDSCs has not been thoroughly elucidated to date.MethodsMDSCs or granulocytic MDSCs (G-MDSCs) were isolated by microbeads and flow cytometry. Bone marrow derived G-MDSCs were induced by IL-6 and GM-CSF. The expression of lncRNA Pvt1 was measured by qRT-PCR. Specific siRNA was used to knockdown the expression of lncRNA Pvt1 in G-MDSCs.ResultsIn this study, we found that knockdown of lncRNA Pvt1 significantly inhibited the immunosuppressive function of G-MDSCs in vitro. Additionally, lncRNA Pvt1 knockdown reduced the ability of G-MDSCs to delay tumor progression in tumor-bearing mice in vivo. Notably, lncRNA Pvt1 was upregulated by HIF-1α under hypoxia in G-MDSCs.ConclusionsTaken together, our results demonstrate a critical role for lncRNA Pvt1 in regulating the immunosuppression activity of G-MDSCs, and lncRNA Pvt1 might thus be a potential antitumor immunotherapy target.

Highlights

Myeloid-derived suppressor cells (MDSCs) participate in tumor-elicited immunosuppression by dramatically blocking T-cell-induced antitumor responses, thereby influencing the effectiveness of cancer immunotherapies
plasmacytoma variant translocation 1 (Pvt1) is highly expressed in tumor-expanded granulocytic MDSCs (G-MDSCs) By comparing expression profile of Long noncoding RNAs (lncRNAs) between G-MDSCs isolated from tumor tissues of Lewis tumor-bearing (TB) mice and spleens from corresponding wild-type (WT) C57BL/6 mice using array-based lncRNA profiling, a large number of lncRNAs were found to be highly expressed in TB mice compared with WT mice
In this study, we report for the first time that Hypoxiainducible factor-1α (HIF-1α) upregulates Pvt1 expression in G-MDSCs under hypoxia

Summary

Introduction

Myeloid-derived suppressor cells (MDSCs) participate in tumor-elicited immunosuppression by dramatically blocking T-cell-induced antitumor responses, thereby influencing the effectiveness of cancer immunotherapies. Treatments that alter the differentiation and function of MDSCs can partially restore antitumor immune responses. Myeloid-derived suppressor cells (MSDCs) represent a heterogeneous population of immature myeloid cells (IMCs) and comprise myeloid progenitors and precursors of granulocytes, macrophages and dendritic cells (DCs), which are a type of immune-suppressive cell that suppresses T cell function [1,2,3]. IMCs quickly differentiate into mature granulocytes, macrophages or DCs after being generated in the bone marrow. Under pathological conditions, such as cancer, infection, inflammation or autoimmune conditions, IMCs can be blocked from differentiation into mature myeloid cells, resulting in expansion of MDSCs [4,5,6].

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