Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

Abstract

The immune system plays a critical role in cancer progression and response to therapy. However, the immune system can be compromised during the neoplastic process. Notably, the myeloid lineage, which gives rise to granulocytic cells, including neutrophils, is a well-recognized target of tumor-mediated immune suppression. Ordinarily, granulocytic cells are integral for host defense, but in neoplasia the normal process of granulocyte differentiation (i.e., granulopoiesis) can be impaired leading instead to the formation of granulocytic (or PMN)-myeloid-derived suppressor cells (MDSCs). Such cells comprise various stages of myeloid differentiation and are defined functionally by their highly pro-tumorigenic and immune suppressive activities. Thus, considerable interest has been devoted to impeding the negative contributions of PMN-MDSCs to the antitumor response. Understanding their biology has the potential to unveil novel therapeutic opportunities to hamper PMN-MDSC production in the bone marrow, their mobilization, or their effector functions within the tumor microenvironment and, therefore, bolster anticancer therapies that require a competent myeloid compartment. In this review, we will highlight mechanisms by which the neoplastic process skews granulopoiesis to produce PMN-MDSCs, summarize mechanisms by which they execute their pro-tumorigenic activities and, lastly, underscore strategies to obstruct their role as negative regulators of antitumor immunity.

Keywords: antitumor immunity; immune suppression; immunotherapy; polymorphonuclear myeloid-derived suppressor cells; tumor progression.

Figure 1

Transcriptional regulators of PMN-MDSCs. Three regulatory axes of PMN-MDSC development or function are depicted. Left to right: PLCγ2 and Dkk1 have been shown to decrease β-catenin signaling, increasing PMN-MDSC burden. STAT3 signaling can be activated by stromal- or tumor-derived factors such as IL-6 or G-CSF, enhancing C/EBPβ expression. STAT3 activation can also inhibit IRF8 expression. Both axes lead to an increase in PMN-MDSCs, although it remains to be determined whether there is crosstalk between the C/EBPβ and IRF8 pathways. Stromal- or tumor-derived GM-CSF engagement leads to STAT5 activation, which inhibits IRF8 expression, an effect that can be overcome by Pak2-mediated inhibition of STAT5. Legend: nodes shown in red or blue enhance or block PMN-MDSCs, respectively; arrows shown in red or blue inhibit or activate its downstream target, respectively.