Myeloid-Derived Suppressor Cells as a Potential Biomarker and Therapeutic Target in COVID-19

Abstract

Clinical presentations of COVID-19 are highly variable, yet the precise mechanisms that govern the pathophysiology of different disease courses remain poorly defined. Across the spectrum of disease severity, COVID-19 impairs both innate and adaptive host immune responses by activating innate immune cell recruitment, while resulting in low lymphocyte counts. Recently, several reports have shown that patients with severe COVID-19 exhibit a dysregulated myeloid cell compartment, with increased myeloid-derived suppressor cells (MDSCs) correlating with disease severity. MDSCs, in turn, promote virus survival by suppressing T-cell responses and driving a highly pro-inflammatory state through the secretion of various mediators of immune activation. Here, we summarize the evidence on MDSCs and myeloid cell dysregulation in COVID-19 infection and discuss the potential of MDSCs as biomarkers and therapeutic targets in COVID-19 pneumonia and associated disease.

Keywords: COVID-19; MDSC; biomarkers; immunity; immunology.

Figure 1

Mechanisms of MDSC-induced immune suppression and development of hyper-inflammation activation in COVID-19. Several mechanisms likely contribute to the MDSC-induced immune suppression and development of hyper-inflammation activation seen in patients with COVID-19. Delayed production of type I interferon leading to enhanced release of monocyte chemoattractants by alveolar epithelial cells leading to sustained recruitment of MDSCs into the lungs. TGFβ and IL-10 release by MDSCs can induce further inflammatory programs in resident (M2) macrophages while recruiting inflammatory monocytes, as well as granulocytes and lymphocytes from circulation. Signaling through activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathways is necessary for MDSC expansion. Increased HIF1α expression can induce the transcription of inflammation related genes. The effector mechanisms employed by MDSCs to control immune cell subsets depend on the MDSC subtype with PMN-MDSCs mainly use reactive oxygen species (ROS) and arginase I, whereas M-MDSCs use inducible nitric oxide synthase (iNOS) and arginase I to dampen bystander cells. Increased PDL1 expression on recruited macrophages and MDSCs can directly decrease antigen-specific T-cell activation through interactions with the PD-1 receptor on T-cells. Increased signaling through the Galectin-9 and Tim-3 pathway can lead to the inhibition of Th1 or CD8+ T cell responses. Increased production of TGFb, ROS and L-arginine production by MDSC can inhibit the function of NK and CD8+ T cells during disease progression. Activated MDSCs contribute to the COVID-19 cytokine storm by releasing high amounts of pro- inflammatory cytokines.