Immune dysregulation in myelodysplastic syndrome: Clinical features, pathogenesis and therapeutic strategies

Myelodysplastic syndrome (MDS) is a heterogeneous hematological malignancy, characterized by cytopenia and accompanied by a risk of transformation into acute myeloid leukemia (AML). Epidemiological studies for decades have shown association between autoimmune diseases (AIDs) and MDS. Specifically, patients with antecedent AIDs tends to have an increased risk of developing MDS, and these patients display different clinical characteristics and outcomes. Importantly, immune dysregulation has been the common driving force between MDS and AIDs pathogenesis. Both innate and adaptive immune systems are overly active in the hematopoietic niche of MDS. It has been observed that in addition to many cytokines secreted in the bone marrow (BM) microenvironment, almost all types of immune cells and their downstream signaling pathways participate in MDS pathogenesis and evolution. Currently, growth factor therapy and hypomethylating agents (HMAs), along with supportive care, are the mainstay for MDS treatment. As information about the contribution of immune system has started emerging in different subtypes of MDS, we need to highlight the value of immunomodulatory therapies. Immune activation seems to participate specifically in the development of lower-risk MDS, and therefore, use of immunosuppressive therapies would be an ideal treatment option for this type. However, in high-risk MDS, escape from immune surveillance appears to contribute to its progression, and thus, several immune-activating treatment options, including immune checkpoint inhibitors and vaccines, are being considered. HMAs have been approved for use in treating high-risk MDS for many years based on their cytotoxicity, but since they also display an epigenetic-immunomodulatory role, they can be an option for lower-risk MDS. Thus, in this review, we discuss the immune dysregulation in MDS, including its clinical features, pathogenic mechanism and immunomodulatory therapeutic options.