P704: aberrant immune microenvironment in bone marrow of myelodysplastic syndrome patients drives a suppressive phenotype

Background: The Myelodysplastic syndromes (MDS) comprise a heterogeneous disease of the bone marrow (BM) characterized by cytopenias due to aberrant stem cells and ineffective hematopoiesis. Patients face increased morbidity and mortality from infection and/or bleeding, while having a high propensity for leukemic transformation. It is evident that aberrant chromosomal and genetic lesions are the key drivers of MDS pathogenesis, which also contributes towards chronic activation of the innate immune response and a hyperinflammatory BM microenvironment. Various types of immune cells like monocytes, dendritic cells, myeloid-derived suppressor cells (MDSCs), T cells, and NK cells add to both the aberrant cytokines and cell-cell interactions within the BM microenvironment. Efforts at modulation of exhaustion signals, thought to contribute to progression in MDS, have been largely ineffective. An in-depth understanding in particular of the NK and T cell regulation and role in immune surveillance of the MDS clone and effects on hematopoiesis is critical in order to provide clues about their role in MDS pathophysiology and progression and identify targets for immunotherapies. Aims: To investigate the immune landscape of BM to capture the dysregulation in myeloid and lymphoid cell compartment. Methods: The BM myeloid and lymphoid cell compartment of MDS patients was profiled by mass cytometry (CyTOF) and compared with age-matched healthy controls. Patients were further categorized into Low-risk (LR) MDS and High-risk (HR) MDS patients based on the IPSS-R score. All the patients included in this study were treatment naïve. Results: We observed highly dysregulated Tregs, NK-cells, CD8T-cells, and γδT-cells in MDS-BM. Importantly, segregating MDS patients based on the disease-category reveals a higher frequency of γδT-cells and NK-cells in lower-risk (LR)-MDS patients compared to healthy individuals. Frequencies of total CD8T-cells or CD4T-cells between LR and higher-risk (HR)-MDS were comparable. However, CD8T-cells exhibit massive expansion of effector memory and terminally differentiated memory CD8T-cells compared to naïve and central memory. CD56-CD16+ NK-cells (matured developmental stage), was significantly expanded with peak abundance in LR-MDS patients and displayed an activated phenotype with elevated CD69, ICOS, Tim-3, and CD95/FasR expressions. The frequency of CD56- CD16+ NK cells positively correlated (p<0.01) with IPSS-R score, cytogenetic risk, and the need for platelet transfusions specifically in LR-MDS patients. In addition, HR-MDS patients exhibit a significantly reduced proportion of classical-monocytes but manifest a higher proportion of intermediate-monocytes and conventional dendritic cells (cDC1) compared to LR-MDS patients and healthy individuals. We also observed the expansion of Monocytic-Myeloid-Derived Suppressor Cells (Mo-MDSCs) in MDS-BM (HR>LR-MDS p value<0.05). Summary/Conclusion: This study suggests that NK-cells and T-cells are activated and dysregulated in the BM early on in the disease-onset suggesting a pathogenic role and may contribute to impeding hematopoiesis. Aberrant myeloid cell-subsets point towards a hyperinflammatory and immunosuppressive phenotype in HR-MDS patients which may facilitate impaired anti-leukemic activity and MDS progression. Additional studies are underway to further characterize the immune-landscape in treatment-naive and treated-MDS patients and to study the interaction of different immune components with MDS blast cells. Keywords: Immune reconstitution, Myelodysplastic syndrome, Bone marrow microenvironment