Bone Marrow Immune Microenvironment in Myelodysplastic Syndromes

Olga Kouroukli, Argiris Symeonidis, Periklis Foukas, Myrto-Kalliopi Maragkou, Eleni P Kourea, Olga Kouroukli, Argiris Symeonidis, Periklis Foukas, Myrto-Kalliopi Maragkou, Eleni P Kourea

Abstract

The BM, the major hematopoietic organ in humans, consists of a pleiomorphic environment of cellular, extracellular, and bioactive compounds with continuous and complex interactions between them, leading to the formation of mature blood cells found in the peripheral circulation. Systemic and local inflammation in the BM elicit stress hematopoiesis and drive hematopoietic stem cells (HSCs) out of their quiescent state, as part of a protective pathophysiologic process. However, sustained chronic inflammation impairs HSC function, favors mutagenesis, and predisposes the development of hematologic malignancies, such as myelodysplastic syndromes (MDS). Apart from intrinsic cellular mechanisms, various extrinsic factors of the BM immune microenvironment (IME) emerge as potential determinants of disease initiation and evolution. In MDS, the IME is reprogrammed, initially to prevent the development, but ultimately to support and provide a survival advantage to the dysplastic clone. Specific cellular elements, such as myeloid-derived suppressor cells (MDSCs) are recruited to support and enhance clonal expansion. The immune-mediated inhibition of normal hematopoiesis contributes to peripheral cytopenias of MDS patients, while immunosuppression in late-stage MDS enables immune evasion and disease progression towards acute myeloid leukemia (AML). In this review, we aim to elucidate the role of the mediators of immune response in the initial pathogenesis of MDS and the evolution of the disease.

Keywords: BM; CHIP; HSC niche; MDS; MDSC; immune dysregulation; immunosuppression; inflamm-aging; microenvironment; pathogenesis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(1) Megakaryocyte support the preservation of HSC quiescence, through the secretion of CXCL4, TGF-β and TPO. (2) Tregs also contribute to HSC quiescence by generating adenosine, which protects HSCs from oxidative stress. (3) Macrophages express DARC, whose interaction with CD82 on the surface of HSCs restrains their proliferative activity. (4) a-SMA(+) macrophages are capable of COX-2-mediated PGE2 production that maintains low ROS levels in HSCs. (5) Macrophages additionally hinder HSC mobilization through the induction of CXCL12 by stromal cells. (6) Dendritic cells further aid HSC retention in the BM via regulation of vascular permeability and endothelial CXCR2 signaling. HSC inactive, quiescent state inhibits self-renewal and differentiation. (CXCL4 = C-X-C motif ligand 4, CXCL12 = C-X-C motif chemokine ligand 12, CXCR2 = CXC chemokine receptor 2, DARC = Duffy antigen/receptor for chemokines, DC = Dendritic cell, HSC = Hematopoietic stem cell, MK = Megakaryocyte, MΦ = Macrophage, PGE2 = Prostaglandin E2, ROS = Reactive oxygen species, TGF-β = Transforming growth factor beta, TPO = Thrombopoietin, Treg = T regulatory cell).
Figure 2
Figure 2
In the aged BM, there is increased number of pro-inflammatory cytokines that act on HSC receptors (TLRs, TNFRs, IFNRs, IL-27Rα). Various abnormally activated pathways in HSCs (listed above) link HSC senescence and BM inflammation. The overstimulated HSCs are myeloid-biased. Immune cell alterations in the senescent BM are consistent with myeloid skewing. Aged macrophages drive platelet bias via IL-1β. Plasma cells are increased and induce myelopoiesis. Increased NK cells and ABCs in the aged BM lead to TNFα-mediated impairment of B lymphopoiesis. (ABC = Age-associated B cell, AIM2 = Absent in melanoma 2, C-GAS-STING = Cyclic guanosine monophosphate-adenosine monophosphate synthase—Stimulating interferon gene, CLP = Common lymphoid progenitor, CMP = Common myeloid progenitor, DAMPs = Damage-associated molecular patterns, HSC = Hematopoietic stem cell, IFNR = Interferon receptor, IL-1β = Interleukin-1 beta, IL-6 = Interleukin-6, IL-18 = Interleukin-18, IL-27Rα = Interleukin-27 receptor alpha, MΦ = Macrophage, NLRP3 = NOD-, LRR- and pyrin domain-containing protein 3, NK = Natural killer, TGF-β = Transforming growth factor beta, TLR = Toll-like receptor, TNF-α = Tumor necrosis factor-alpha, TNFR = Tumor necrosis factor receptor, Rantes = Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted, RBCs = Red blood cells).
Figure 3
Figure 3
Low-risk MDS is characterized by a pro-apoptotic and cytotoxic microenvironment. (1) Apart from the elevated number of pro-inflammatory cytokines in the BM, there is increased responsiveness of the MDS cells that express the pro-apoptotic receptors, Fas and TNFR1. (2) CD8+ T-cells target MDS cells and exhibit augmented cytotoxicity, partly due to the expression of NKG2D and CD244 receptors. However, CD8+ T-cells suppress also normal hematopoietic cells and inhibit hematopoiesis. (3) MDS myeloid progenitor cells, derived from MDS HSCs, express the prophagocytic molecule CRT, possibly representing the main factor of cellular loss in low-risk MDS. (CRT = Calretinin, Fas = Fas receptor, FasL = Fas ligand, HSCs = Hematopoietic stem cells, IL-1β = Interleukin-1 beta, IL-7 = Interleukin-7, IL-8 = Interleukin-8, IL-12 = Interleukin-12, MΦ = Macrophage, NK2GD = Natural killer group 2D, TNFR1 = Tumor necrosis factor receptor 1).
Figure 4
Figure 4
In contrast to low-risk MDS, immune evasion and decreased apoptosis enable clonal expansion in the BM of high-risk MDS. (1) In high risk MDS cells, there is a preferential expression of the anti-apoptotic TNFR2 and the anti-phagocytic CD47. (2) Macrophages acquire a M2 phenotype and produce IL-10. (3) Tregs expand and contribute to immune suppression. (4) CD8+ T-cell exhaustion is mediated by the expression of immune checkpoint molecules PD-1, PD-L1 and TIM3. (5) TIM3-ligand, Gal9, is expressed on MDSCs, which are induced upon binding of alarmin S100A9 on their CD33 receptor. MDSCs are increased and provide a large amount of immunosuppressive cytokines in the BM of high risk MDS. (6) MSCs are implicated in the anti-inflammatory microenvironment as they are a source of S100A9 and inhibitory molecules, such as TGF-β1, which suppresses DC maturation. (7) NK cells receive inadequate support from MSCs and exhibit impaired maturation, numerical and functional deficiency. (GAL9 = Galectin9, DCs = Dendritic cells, IL-10 = Interleukin-10, M2 MΦ = M2 macrophage, MDSCs = Myeloid-derived suppressor cells, MSCs = Mesenchymal stromal cells, NK = Natural killer, NO = Nitric oxide, PD-1 = Programmed cell death protein 1, PD-L1 = Programmed death-ligand 1, S100A9 = S100 calcium-binding protein A9, SIRPa = Signal regulatory protein alpha, TGF-β = Transforming growth factor-beta, TIM3 = T-cell immunoglobulin and mucin-domain containing 3, TNFR2 = Tumor necrosis factor receptor 2, Tregs = T regulatory cells).

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