Interferon Regulatory Factor 4 Regulates the Development of Polymorphonuclear Myeloid-Derived Suppressor Cells Through the Transcription of c-Myc in Cancer.

Quan Yang,Jinxue Yang,Yuanfa Feng,Shihao Xie,Hongyan Xie,Jiale Qu,Xiaohao Hu,Anqi Xie,Yiqiang Zhu,Haixia Wei,Jun Huang,Huaina Qiu,Lu Zhou,Wenjuan Qin,Xing Li

doi:10.3389/fimmu.2021.627072

Abstract

The accumulation of myeloid-derived suppressor cells (MDSCs) is one of the major obstacles to achieve an appropriate anti-tumor immune response and successful tumor immunotherapy. MDSCs in tumor-bearing hosts are primarily polymorphonuclear (PMN-MDSCs). However, the mechanisms regulating the development of MDSCs remain poorly understood. In this report, we showed that interferon regulatory factor 4 (IRF4) plays a key role in the development of PMN-MDSCs, but not monocytic MDSCs. IRF4 deficiency caused a significant elevation of PMN-MDSCs and enhanced the suppressive activity of PMN-MDSCs, increasing tumor growth and metastasis in mice. Mechanistic studies showed that c-Myc was up-regulated by the IRF4 protein. Over-expression of c-Myc almost abrogated the effects of IRF4 deletion on PMN-MDSCs development. Importantly, the IRF4 expression level was negatively correlated with the PMN-MDSCs frequency and tumor development but positively correlated with c-Myc expression in clinical cancer patients. In summary, this study demonstrated that IRF4 represents a novel regulator of PMN-MDSCs development in cancer, which may have predictive value for tumor progression.

Highlights

The immunosuppressive state of individuals with tumors is a key factor in limiting the body’s anti-tumor immune response
We found that the expression of interferon regulatory factor 4 (IRF4) in the Myeloid-derived suppressor cells (MDSCs) of the tumor group was significantly down-regulated (Figure 1A)
The western blot (WB) further confirmed that expression of IRF4 in T-MDSCs was clearly down-regulated compared with N-MDSCs (Figure 1C)

Summary

Introduction

The immunosuppressive state of individuals with tumors is a key factor in limiting the body’s anti-tumor immune response. Myeloid-derived suppressor cells (MDSCs) has well known roles in the suppression of anti-tumor immunity in tumor-bearing hosts [2, 3]. MDSCs are defined as different subpopulations with specific phenotypes in human with clear immunosuppressive capacities, which have three subsets: M-MDSCs (HLA-DR-CD11b+CD33hi), PMN-MDSCs (HLADR-CD11b+CD33low), and e-MDSC (Lin-HLA-DR-CD33+) [8, 9]. These subsets differ with respect to their function, tissue distribution, and regulatory mechanism [8, 10, 11]. Some important transcription factors and signaling pathways have been identified to regulate the differentiation of tumor-derived MDSCs [14,15,16], the concrete mechanisms remain to be fully elucidated

Methods

Results

Conclusion