The downregulation of type I IFN signaling in G-MDSCs under tumor conditions promotes their development towards an immunosuppressive phenotype

Yingying Sun,Shu Jiang,Chao Shang,Boya Xu,Yawei Wang,Yan Mo,Dake Wang,Yueshuang Ke,Xiaoqing Han,Xianlu Zeng

doi:10.1038/s41419-021-04487-w

Abstract

Tumors modify myeloid cell differentiation and induce an immunosuppressive microenvironment. Granulocytic myeloid-derived suppressor cells (G-MDSCs), the main subgroup of myeloid-derived suppressor cells (MDSCs), are immature myeloid cells (IMCs) with immunosuppressive activity and exist in tumor-bearing hosts. The reason why these cells diverge from a normal differentiation pathway and are shaped into immunosuppressive cells remains unclear. Here, we reported that the increase of granulocyte colony-stimulating factor (G-CSF) in mouse serum with tumor progression encouraged G-MDSCs to obtain immunosuppressive traits in peripheral blood through the PI3K-Akt/mTOR pathway. Importantly, we found that downregulation of type I interferon (IFN-I) signaling in G-MDSCs was a prerequisite for their immunosuppressive effects. Suppressor of cytokine signaling (SOCS1), the action of which is dependent on IFN-I signaling, inhibited the activation of the PI3K-Akt/mTOR pathway by directly interacting with Akt, indicating that the differentiation of immunosuppressive G-MDSCs involves a transition from immune activation to immune tolerance. Our study suggests that increasing IFN-I signaling in G-MDSCs may be a strategy for reprograming immunosuppressive myelopoiesis and slowing tumor progression.

Highlights

Avoiding immune destruction is an important characteristic of cancer cells [1]
Downregulation of IFN-I signaling is a prerequisite for Granulocytic myeloid-derived suppressor cells (G-myeloid-derived suppressor cells (MDSCs)) to obtain immunosuppressive function We explored whether granulocyte colonystimulating factor (G-CSF) affects IFN-I signaling in G-MDSCs
We detected the expression of IFN-I signaling in mo-MDSCs, and the results showed that the IFN-I signaling in mo-MDSCs was downregulated (Supplementary Fig. 8), suggesting that the downregulation of IFN-I signaling under tumor conditions is necessary for the formation of an immunosuppressive microenvironment

Summary

INTRODUCTION

Avoiding immune destruction is an important characteristic of cancer cells [1]. Tumor conditions can induce the generation of multiple immunosuppressive cells (regulatory T cells (Tregs), tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs), etc.) [2]. MDSC expansion and differentiation are associated with cytokines secreted by tumor cells and tumor stroma cells [8,9,10] Proinflammatory mediators, such as IL-1β, IL-6, and PGE2, affect the normal differentiation of IMCs and regulate MDSC accumulation [11]. The downregulation of IFN-I signaling expression of immunosuppressive gene in G-MDSCs led to the activation of the PI3K-Akt/mTOR pathway, To explore the nature of IMC differentiation into immunosuppressive and SOCS1 which is dependented on IFN-I signaling regulated the G-MDSCs, transcriptome sequencing was performed. Differindicate that the downregulation of IFN-I signaling in G-MDSCs is ential expression analysis of the sequencing data revealed the gene necessary to obtain immunosuppressive function, suggesting that expression patterns of peripheral blood G-MDSCs from tumorupregulation of IFN-I signaling may attenuate tumor progression.

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS