PATTERN OF INNATE IMMUNITY IN PATIENTS AFFECTED BY MYELODYSPLASTIC SYNDROME (MDS) EITHER BEFORE ANDAFTER HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT)

Myelodysplastic syndromes (MDS) are a heterogenous group of myeloid neoplasms that primarily affect elderly people and, in the context of population aging, MDS incidence is set to increase substantially. MDS patients have a variable risk of progression to acute myeloid leukemia (AML) and are characterized by ineffective hematopoiesis, cytogenetic changes and molecular abnormalities. In the past decade significant efforts have been made to understand the pathophysiology of MDS. It has become increasingly evident that early driver mutations dictate the clonal proliferation of myelodysplastic cells and the trajectories of evolution of MDS with distinct clinical phenotypes. However, the definite pathogenetic mechanism of MDS is still not fully clarified, hindering the clinical decision-making process. Indeed, frontline pharmacological therapies, mainly based on the use of hypomethylating agents (HMAs), are not curative and the current patient risk stratification, aimed at identifying MDS patients with a higher risk to progress to AML, ineffectively predicts patient prognosis and response to therapies. Moreover, the only curative treatment for high-risk MDS patients is hematopoietic stem cell transplant (HSCT), however, only a small portion of patients is eligible for it. The dysregulation and dysfunction of the immune system with the acquisition of an immunosuppressive signature are emerging as important characteristics in the prognosis and the clinical outcome of MDS patients. Indeed, although MDS patients are generally lymphopenic, cellular immunity seems to be up-regulated in low-risk MDS patients and impaired in high-risk MDS patients. For this reason, a deeper investigation of the immune populations is essential to identify new clinically relevant MDS prognostic and/or predictive markers. Furthermore, the alteration of the bone marrow niche together with the cytokine unbalance further contributes to increase genomic instability, to repress normal hematopoiesis and to determine an immune tolerant microenvironment in the of MDS patients. Despite this evidence, the primary orchestrators of the dysregulated MDS microenvironment have not yet been identified. In this context, innate lymphoid cells (ILCs) are emerging as important actors in the pathophysiology of different cancers, by generating a suppressive and tolerant environment. Indeed, we and others demonstrated that ILC subset distribution and functions in AML are altered and contribute to immunotolerance. However, a comprehensive immune-phenotypic characterization of ILCs aiming at investigating their involvement in MDS pathogenesis, progression and in response to the main therapeutic interventions is still lacking. The solely ILC subpopulation investigated in MDS is represented by NK cells. However, the experimental data available nowadays show contradictions. In this PhD thesis, we aim at performing a deep characterization of cytotoxic, namely NK cells, and helper ILC frequency, phenotype and function in a large cohort of MDS and AML patients during the natural history of the disease and in the response to HMA treatment and also their immune reconstitution (IR) upon haploidentical-HSCT. Our data demonstrated that MDS patients, and especially those with high blast counts, have a deficient ILC-poiesis characterized by the accumulation of ETP2s, a preferential differentiation toward dysfunctional ILC1s, accompanied by the reduction of total NK cells, with a skewing toward less differentiated NK cell subsets that are functionally impaired. This pathological ILC differentiation is related to a defect endowed by ILC progenitors, which are able to modify the morphology and functional properties of MSCs in the BM niche.