A recent review published in Frontiers in Immunology discussed the manifestations and roles of immune dysregulation in myelodysplastic syndrome (MDS) and summarized the latest progress of immunotherapy in this area.
The authors used the “Yin-Yang theory” to characterize the role that immune dysregulation plays in the pathogenesis of MDS. “Immune dysregulation of MDS with different risk stratification can be summarized by an advanced philosophical thought ‘Yin-Yang theory’ in ancient China, meaning that [lower-risk MDS (LR-MDS)] and [higher-risk MDS (HR-MDS)] are opposite to each other, have a balance of waning and waxing, depend on each other and may transform into its opposite side under given conditions,” the researchers explained in their report.
Research has demonstrated that LR-MDS is predominantly characterized by immune hyperfunction, with increased levels of pro-inflammatory cytokines, such as interferon-gamma, interleukin 8 (IL-8), IL-12, and IL-17, which lead to increased apoptosis of normal hemopoietic stem cells (HSCs) in bone marrow (BM). CD8+T lymphocytes are generally more active and induce intramedullary apoptosis in patients with LR-MDS, whereas immunosuppressive T-regulatory cells (Treg) are decreased.
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In contrast, studies have demonstrated that HR-MDS is mainly characterized by immune suppression and immune escape. CD8+T lymphocytes are often significantly decreased in patients with HR-MDS, and this has been linked to overexpression of programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) in the tumor microenvironment, facilitating the escape of tumor cells from host immunosurveillance. The number and activity of Treg cells are increased in HR-MDS, further promoting immune escape and enabling transformation to acute myeloid leukemia (AML).
In both patients with LR-MDS and HR-MDS, studies have shown that the levels of tumor necrosis factor α (TNF-alpha) and TNF-beta are increased and contribute to disease development. In particular, TNF-beta appears to have differential effects on immune status in MDS that depend on the specific cells and microenvironment.
The review also discusses the varied roles of other cell types, including Th17, Th22, natural killer (NK), dendritic, mesenchymal, myeloid-derived suppressor and other immune cells, in LR-MDS and HR-MDS. The authors also highlight how immune dysregulation in some patients with MDS is dynamic, alternating between immune hyperfunction and immune suppression, sometimes demonstrating coexistence of the states.
Given the role of immune dysregulation in MDS, immunotherapy may be one of the most promising treatments. Immunosuppressive therapy — in particular antithymocyte globulin (ATG), ciclosporin A (CSA), and the combination of ATG and CSA — has demonstrated good clinical efficacy and safety in patients with LR-MDS. Some monoclonal antibodies, such as alemtuzumab and TNF-beta inhibitors, have also demonstrated therapeutic effect in LR-MDS.
Hypomethylating agents (HMAs), such as decitabine and azacitidine, promote expression of antitumor immunity genes, enhance tumor immunogenicity, and activate a variety of immune cells in HR-MDS and AML. Immune activation therapy, including immune checkpoint (PD-L1/PD-1) inhibitors and tumor vaccines, also appear to improve survival of patients with HR-MDS. Studies with monoclonal antibodies, such as MGB453 and ipilimumab, adoptive T-cell transfer therapy (chimeric antigen receptor T [CAR-T] cell, tumor infiltrating lymphocytes [TIL], T cell receptor T cell [TCR-T] therapy), and NK cell adoptive transfer therapy are underway.
“Taken together, we think that a better understanding of the mechanisms and manifestations of immune dysregulation in MDS with different risk stratification can help us to provide a new breakthrough in the area of MDS immunotherapy, and more importantly that it will provide a scientific rationale for clinical trials,” concluded the authors.
Reference
Peng X, Zhu X, Di T, et al. The yin-yang of immunity: Immune dysregulation in myelodysplastic syndrome with different risk stratification. Front Immunol. 2022;13:994053. Published September 23, 2022. doi:10.3389/fimmu.2022.994053
