Immune Mechanisms in Myelodysplastic Syndrome

Abstract

Myelodysplastic syndrome (MDS) is a spectrum of diseases, characterized by debilitating cytopenias and a propensity of developing acute myeloid leukemia. Comprehensive sequencing efforts have revealed a range of mutations characteristic, but not specific, of MDS. Epidemiologically, autoimmune diseases are common in patients with MDS, fueling hypotheses of common etiological mechanisms. Both innate and adaptive immune pathways are overly active in the hematopoietic niche of MDS. Although supportive care, growth factors, and hypomethylating agents are the mainstay of MDS treatment, some patients-especially younger low-risk patients with HLA-DR15 tissue type-demonstrate impressive response rates after immunosuppressive therapy. This is in contrast to higher-risk MDS patients, where several immune activating treatments, such as immune checkpoint inhibitors, are in the pipeline. Thus, the dual role of immune mechanisms in MDS is challenging, and rigorous translational studies are needed to establish the value of immune manipulation as a treatment of MDS.

Keywords: Pancytopenia; adaptive immunity; autoimmunity; innate immunity; myelodysplastic syndrome.

Figure 1

Potential mechanism of bone marrow suppression by T-cells. CD8+ T-cells are activated by major histocompatibility complex (MHC)-class I complex on malignant MDS stem cells, which leads to T-cell expansion which in turn suppress hematopoiesis. T-cells secrete proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon gamma (IFN)-γ into the bone marrow microenvironment, which may both hinder hematopoiesis and induce PD-L1 on tumor cells hereby promoting escape from tumor surveillance. Normally, mesenchymal stromal cells (MSC) suppress T-cells activation in the bone marrow by paracrine and cell-to-cell interaction, but these mechanisms may be flawed in myelodysplastic syndrome (MDS).