Signaling pathways involved in MDSC regulation

Abstract

The immune system has evolved mechanisms to protect the host from the deleterious effects of inflammation. The generation of immune suppressive cells like myeloid derived suppressor cells (MDSCs) that can counteract T cell responses represents one such strategy. There is an accumulation of immature myeloid cells or MDSCs in bone marrow (BM) and lymphoid organs under pathological conditions such as cancer. MDSCs represent a population of heterogeneous myeloid cells comprising of macrophages, granulocytes and dendritic cells that are at early stages of development. Although, the precise signaling pathways and molecular mechanisms that lead to MDSC generation and expansion in cancer remains to be elucidated. It is widely believed that perturbation of signaling pathways involved during normal hematopoietic and myeloid development under pathological conditions such as tumorogenesis contributes to the development of suppressive myeloid cells. In this review we discuss the role played by key signaling pathways such as PI3K, Ras, Jak/Stat and TGFb during myeloid development and how their deregulation under pathological conditions can lead to the generation of suppressive myeloid cells or MDSCs. Targeting these pathways should help in elucidating mechanisms that lead to the expansion of MDSCs in cancer and point to methods for eliminating these cells from the tumor microenvironment.

Keywords: Jak/Stat; Myeloid derived suppressor cells (MDSC); PI3K; Ras; TGFβ; Tumor microenvironment.

Figure 1. Signaling pathways involved in regulation of MDSC function

Cytokines produced by hematopoietic and cancer cells bind to their respective cognate receptors leading to phosphorylaton of key tyrosine residues leading to the activation of Ras/Mitogen activated protein kinase (Ras/MAPK), Phosphatidylinositol-3-kinase (PI3K), Janus kinase/Signal transducer activator of transcription (Jak/Stat) and Transforming growth factor β (TGFβ) pathways. This subsequently results in activation of transcription factors (TF). The TF’s then bind to their putative sites on gene promoters leading to activation of genes involved in proliferation, survival and migration of MDSCs. Transcription factor (TF), Stat binding sites (SBS), Smad binding elements (SBE). Macrophage colony stimulating factor (M-CSF), Granulocyte colony stimulating factor (G-CSF), Granulocyte macrophage colony stimulating factor (GM-CSF), Colony stimulating factor 1 receptor (CSF-1R), Granulocyte macrophage colony stimulating factor receptor (GM-CSFR), Granulocyte colony stimulating factor receptor (G-CSFR), Serine/threonine specific kinase (Akt), Suppressor of cytokine signaling (SOCS), Protein inhibitor of activated Stat (PIAS), Protein tyrosine phosphatase (PTP), Extracellular signal regulated kinase (ERK), Receptor regulated Smad (R-SMAD), Mammalian target of rapamycin (mTOR), Phosphatase with tensin homology (PTEN), Tuberous sclerosis complex (TSC), Ras homolog enriched in brain (Rheb), 4E binding protein-1 (4EBP1), Interleukin-6 (IL-6), Prostaglandin E2 (PGE2), Lipopolysaccharide (LPS), Interleukin-1 beta (IL-1b), Glycoprotein 130 (Gp130).

Figure 2. Role of signaling pathways involved in generation, expansion and functional regulation of MDSCs in cancer

Cytokines like macrophage colony stimulating factors (M-CSF) and granulocyte macrophage colony stimulation factor (GM-CSF) are involved during normal myeloid development from hematopoietic stem cells (HSC). Increased production of these cytokines during tumorogenesis interferes with normal myeloid development resulting in the generation of immature myeloid cells (iMC). These iMC generally differentiate into macrophages and granulocytes. However, in presence of factors like IL-6 and IL-1β, iMC differentiate into myeloid derived suppressor cells (MDSCs). Furthermore, cancer cells secrete factors like PGE2 and Cxcl12 that help in the recruitment of MDSC to the TME. Finally, the activation of downstream PI3K/Akt and Jak/Stat signaling pathways regulate the expression of genes like iNOS, IL-10 and arginase that are involved in mediating the immune suppressive function of MDSCs.