Disrupted Innate Lymphoid Cell Poiesis and Immune Dysfunction in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells, characterized by bone marrow dysplasia, peripheral cytopenia, and variable risk of progression to acute myeloid leukemia (AML). MDS display marked clinical and biological heterogeneity, with prognoses ranging from a near normal life to aggressive forms. Despite research advances, MDS pathogenesis is poorly understood, making diagnosis and risk stratification challenging. Growing evidence implicates immune dysfunction as a key contributor to MDS pathophysiology. However, its diagnostic and prognostic relevance remains poorly defined and it is not incorporated into the current clinical scoring systems. In this context, innate lymphoid cells (ILCs), including Natural Killer (NK) cells and helper-ILCs, play critical roles in immune surveillance and shaping immunosuppressive microenvironment in cancers. However, they are largely unexplored in the MDS context. To comprehensively characterize ILC function and ILC-poiesis in MDS, we analyzed bone marrow (BM) samples from risk-stratified patients using an integrated approach combining multi-parametric flow cytometry, multiplexed assays and single-cell RNA sequencing. Our findings reveal that MDS patients, particularly those with poor prognosis, exhibit dysfunctional and exhausted ILCs. This cellular impairment occurs in the context of a chronically inflamed BM microenvironment, contributing to the disruption of the ILC niche, ultimately impairing the effectiveness of the immune surveillance mechanisms.