The CCAAT/Enhancer-Binding Protein Family: Its Roles in MDSC Expansion and Function

Abstract

Immunosuppressive cells have been highlighted in research due to their roles in tumor progression and treatment failure. Myeloid-derived suppressor cells (MDSCs) are among the major immunosuppressive cell populations in the tumor microenvironment, and transcription factors (TFs) are likely involved in MDSC expansion and activation. As key regulatory TFs, members of the CCAAT/enhancer-binding protein (C/EBP) family possibly modulate many biological processes, including cell growth, differentiation, metabolism, and death. Current evidence suggests that C/EBPs maintain critical regulation of MDSCs and are involved in the differentiation and function of MDSCs within the tumor microenvironment. To better understand the MDSC-associated transcriptional network and identify new therapy targets, we herein review recent findings about the C/EBP family regarding their participation in the expansion and function of MDSCs.

Keywords: C/EBPs; differentiation; immunosuppression; myeloid-derived suppressor cells; transcription factors.

Figure 1

Regulation of C/EBPβ in MDSCs. Stimulation by G-CSF, GM-CSF, IL-6, or other factors strongly induces C/EBPβ expression in MDSCs. The JAK-STAT3 signaling pathway may function as an upstream regulator of C/EBPβ. Three isoforms of C/EBPβ are generated from its mRNA through a ribosomal scanning mechanism. In addition, C/EBPβ cooperates with p-STAT3 or NF-κB by sharing the same target genes. On the one hand, C/EBPβ LAP* and LAP function as transcriptional activators of the expression of immunosuppressive genes such as Arg-1, NOS2, NOX2, or COX2, whereas LIP attenuates function by blocking LAP and LAP* signaling. On the other hand, C/EBPβ affects the differentiation and expansion of MDSCs by regulating IL-6, CSFs, CSFRs, MMPs, or other factors.

Figure 2

Cooperation among the C/EBP family members in MDSCs. The C/EBP family members cooperatively regulate MDSCs. (A) Under pathological conditions, C/EBPα might relatively downregulate, but C/EBPβ, C/EBP-δ, and CHOP might strongly upregulate in MDSCs (, , , –37, 50, 57). (B) There is a possible switch between C/EBPα and C/EBPβ in MDSCs, that is sufficient to turn on or off target promoter (4, 8). (C) C/EBPβ exists as three isoforms, and one cooperation model is promoting activation of LAP or LAP*. For example, CHOP binds to LIP and to sequester LAP or LAP* in MDSCs (53, 56).