Transcriptional regulation of myeloid-derived suppressor cells

Abstract

Myeloid-derived suppressor cells are a heterogeneous group of pathologically activated immature cells that play a major role in the negative regulation of the immune response in cancer, autoimmunity, many chronic infections, and inflammatory conditions, as well as in the regulation of tumor angiogenesis, tumor cell invasion, and metastases. Accumulation of myeloid-derived suppressor cells is governed by a network of transcriptional regulators that could be combined into 2 partially overlapping groups: factors promoting myelopoiesis and preventing differentiation of mature myeloid cells and factors promoting pathologic activation of myeloid-derived suppressor cells. In this review, we discuss the specific nature of these factors and their impact on myeloid-derived suppressor cell development.

Keywords: Rb1; S100A9; STAT3; STAT6.

Figure 1.. MDSC differentiation is regulated by different signals.

MDSCs arise from CMP and GMP. However, the presence of tumor-derived growth factors (Signal 1) drives the expansion of monocytic and granulocytic precursors. These precursors require an activation signal (Signal 2) to acquire a suppressive phenotype to give rise to bona fide PMN-MDSC and M-MDSC. These 2 types of signals also inhibit myeloid cell differentiation into terminally differentiated cells, such as DC and MΦ. HSC, Hematopoietic stem cell.

Figure 2.. Transcription factors and signaling pathways involved in MDSC expansion.

There are several cytokines and transcriptional factors/regulators involved in the expansion and differentiation of MDSC. The transcription factors have a certain specificity in regulating the MDSC subsets. Details are provided in the text. RTKs, Receptor tyrosine kinases.

Figure 3.. Pathways involved in the acquisition of a suppressive phenotype by MDSC.

A large array of proinflammatory factors is involved in the conversion of immature myeloid cells into suppressive cells. Several pathways have been involved in the conversion of PMN-MDSC and M-MDSC (NF-κB, STAT6, and ER stress pathways), whereas some are more specific to PMN-MDSC (STAT3) or M-MDSC (COX2). The STAT1 pathway may have opposite effects on MDSC subsets, promoting M-MDSC-suppressive activity while inhibiting the activity of PMN-MDSC. ARG-1, Arginase-1; PNT, peroxynitrite.