Abstract
Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells with major regulatory functions and rise during pathological conditions, including cancer, infections and autoimmune conditions. MDSC expansion is generally linked to inflammatory processes that emerge in response to stable immunological stress, which alter both magnitude and quality of the myelopoietic output. Inability to reinstate physiological myelopoiesis would fall in an “emergency state” that perpetually reprograms myeloid cells toward suppressive functions. While differentiation and reprogramming of myeloid cells toward an immunosuppressive phenotype can be considered the result of a multistep process that originates in the bone marrow and culminates in the tumor microenvironment, the identification of its driving events may offer potential therapeutic approaches in different pathologies. Indeed, whereas expansion of MDSCs, in both murine and human tumor bearers, results in reduced immune surveillance and antitumor cytotoxicity, placing an obstacle to the effectiveness of anticancer therapies, adoptive transfer of MDSCs has shown therapeutic benefits in autoimmune disorders. Here, we describe relevant mechanisms of myeloid cell reprogramming leading to generation of suppressive MDSCs and discuss their therapeutic ductility in disease.
Highlights
Immunologic stress, such as infection and cancer, modifies the magnitude and composition of the hematopoietic output, a feature of immune regulation defined as “emergency” hematopoiesis, to guarantee proper supply of both lymphoid and myeloid cells to increased demand [1]
Under steady-state conditions, myelopoiesis is a strictly regulated process that consists of a series of cell lineage commitments, encompassing sequential steps of differentiation that govern the transition of hematopoietic stem cells (HSCs) to myeloid precursors and to mature immune cells, which is necessary to maintain the physiological levels of circulating neutrophils and monocytes [2]
We recently showed that the retinoic acid-related orphan receptor (RORC1/RORγ) orchestrates emergency myelopoiesis by suppressing negative (Socs3 and Bcl3) and promoting positive (C/EBPβ) regulators of granulopoiesis, as well as the key transcriptional mediators of myeloid progenitor commitment and differentiation to the monocytic/macrophage lineage (IRF8 and PU.1) [9]
Summary
Immunologic stress, such as infection and cancer, modifies the magnitude and composition of the hematopoietic output, a feature of immune regulation defined as “emergency” hematopoiesis, to guarantee proper supply of both lymphoid and myeloid cells to increased demand [1]. From a biochemical and functional perspective, suppressive PMN-MDSCs are characterized by the production of reactive oxygen species (ROS) and arginase 1 (Arg1), whereas M-MDSCs predominantly express the inducible nitric oxide synthase (iNOS) gene and produce nitric oxide (NO) Both pathways promote depletion of the amino acid l-arginine and down-regulation of T cell receptor (TCR) ζ-chain expression, leading to cell cycle arrest [14]. In some infections, caused either by bacteria (e.g., M. tuberculosis, Staphylococcus aureus) or viruses (e.g., hepatitis B virus/HBV, hepatitis C virus/HCV, human immunodeficiency viruses/HIV), the host’s immune response is not able to remove the pathogen, which instead persists and leads to a chronic inflammatory state In these pathological conditions, the accumulation of MMDSCs is stimulated to restrict T cell effector functions and to recruit Treg cells in order to resolve inflammation and reestablish immune homeostasis [24, 25]. We discuss the role of MDSCs in cancer and autoimmune diseases, highlighting their main suppressor mechanisms and possible therapeutic interventions
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