The immunome profile of myelodysplastic syndrome patients defines different prognostic groups and shows a predictive potential to hypomethylating therapy

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by a variable risk of progression to acute myeloid leukemia (AML). Since the pathogenetic mechanisms are still unknown, the diagnosis of MDS is challenging and risk stratification, mainly based on aspecific clinical parameters, fails to exactly predict the prognosis and the response to the current available frontline therapies, by means of hypomethylating agents (HMAs). Considering the increasingly well-known role of immune dysregulation in MDS pathogenesis and progression, by using high-dimensional flow cytometry, we performed a comprehensive analysis of T and Natural Killer (NK) cells in bone marrow (BM) and peripheral blood (PB) of 154 MDS and AML post-MDS patients before and after HMAs. Data analysis was performed implementing an unsupervised pipeline which combines Phenograph and HDBSCAN algorithms. We identified 5 groups of MDS patients based on their immunological profile. These immunological groups, characterized by different grade of immune dysfunction and inflammation, were related to different prognosis and response to HMA therapy. Moreover, since patients classified within the same category according to existing prognostic scoring systems were subdivided into different immunological groups, we developed a tool to assign a score to the immune dysfunction of MDS patients. This score was integrated to existing prognostic models to refine prognostic assessment and better predict therapy response. Together our data provide evidence that the evaluation of the immune profile of MDS patients is of utmost importance to improve risk stratifications endowing them with predictive potential of HMA treatment response.