Natural killer cell activity and survival after azacitidine treatment in high-risk MDS

The myelodysplastic syndromes (MDS) are a group of myeloid malignancies with diverse presentation, characteristics, and pathological features. A particular area of divergent features in MDS relates to the immune environment. In lower-risk MDS, autoimmune destruction of hematopoietic stem cells plays a role in some cases in the development of cytopenias, similar to what is seen with other bone marrow failure syndromes such as aplastic anemia [1]. Immunosuppressive therapy with agents such as antithymocyte globulin, and immunomodulatory agents like lenalidomide can be employed for many of these patients, and these treatments can frequently result in hematologic responses and/or survival [2,3]. Conversely, in high-risk disease, MDS cells frequently develop mechanisms to evade immune surveillance such as decreasing lymphocyte and NK cell activity, or upregulation of PD-L1 expression, resulting in an environment that allows MDS to persist [4]. In this issue of Leukemia and Lymphoma, Tsirogianni et al. provide further evidence for this phenomena in highrisk MDS. This study elegantly associates impaired NK cell activity and poor prognosis, and preservation of functional NK cell activity with improved survival [5]. Tsirogianni et al. examined patients with high-risk MDS treated with azacitidine, with the aim to identify immune-related predictors of response to azacitidine and predictors of overall survival [5]. The authors first quantitated immune cells, namely T-cells including the regulatory T cell subset, NK cells including NKT cells, and myeloid-derived suppressor cells after exposure to azacitidine. Compared to healthy patient samples, no significant differences in these populations were observed. Further, there was no correlation seen between the percentage of these populations, and outcome. Interestingly, the next set of experiments the authors performed attempted to assess the cytotoxicity of the immune cells present in patients [5]. These experiments appeared to reveal that the presence of cytotoxic NK cells plays an important role in survival for these high-risk MDS patients. This was demonstrated through studies in which NK cells were isolated from the peripheral blood of subjects after three to six cycles of therapy with 5-azacitidine. These NK cells were then subjected to standard NK cell cytotoxicity assays using the K562 leukemia cell line. What was discovered was that in patients whose NK cells demonstrated at least a minimum threshold of cytotoxicity, these had a significantly improved survival compared to those patients whose NK cells demonstrated little cytotoxicity. Remarkably, this NK cytotoxicity assay neatly sorted patients into those who survived over 2 years, and those who died within 1 year. This was independent of other prognostic markers including IPSS score. Previous studies have demonstrated that in highrisk MDS, and in AML, NK cells are functionally defective [6,7]. This is the first study in high-risk MDS to demonstrate that NK cell cytotoxicity is correlates with patient survival. However, several questions remain that remain to be addressed. The study did not determine whether azacitidine therapy restores defective NK cell cytotoxicity, or whether in some patients NK cell cytotoxicity is preserved, while in others, azacitidine may result in suppression of NK cell cytotoxicity. Therefore, future studies are required. A logical future study would be to prospectively follow NK cell cytotoxicity preand post-azacitidine therapy. Other