Disrupted innate lymphoid cell development shapes prognosis and therapy outcomes in myelodysplastic syndrome patients

Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms, with prognoses ranging from mild forms to cases at high risk of progression to Acute Myeloid Leukemia. The current classifications and prognostic scoring systems, mainly based on aspecific clinical parameters, fail to predict the prognosis and the response to hypomethylating agents (HMAs). Although immune dysfunction is emerging as a key factor in MDS, it is not considered in the current patient stratifications. Innate lymphoid cells (ILCs), including Natural Killer (NK) cells and helper-ILCs, appear as important actors in generating a suppressive and tolerant environment in different cancers. However, they are poorly characterized in MDS. METHODS We investigated ILC and progenitor distribution in bone marrow (BM) and peripheral blood samples of MDS patients by multi-parametric flow cytometry. To disclose the impact of MDS blasts on ILC-poiesis, we set up an in vitro BM niche. RESULTS We demonstrated that high-risk MDS patients display ILC progenitor accumulation and a preferential differentiation into dysfunctional ILC1s at the expense of NK cells. HMA therapy partially restores ILC features in responders. Our in vitro data also demonstrated that the pathological ILC distribution is mediated by MDS clones, which disrupt the BM niche. CONCLUSIONS These findings indicate that BM niche alterations in MDS patients disrupt ILC maturation, ultimately impairing immune surveillance.