P727: nk-cell immunoediting by mesenchymal stromal cells in mds

Background: Disorders of the immune system contribute to the pathophysiology and progression of myelodysplastic syndrome (MDS). Cytotoxic Natural Killer (NK) lymphocytes have been extensively studied for their anti-leukemic activity. However, whether the dysplastic bone marrow (BM) in MDS can directly imprint NK cells and hence alter immunosurveillance is still controversial. Extensive characterizations of MDS patients uncovered deep perturbations in the phenotype and function of cytotoxic lymphocyte subsets and of the stromal compartment, in particular mesenchymal stromal cells (MSC), linked with disease predisposition, initiation and progression. However, few studies have been undertaken to characterize the interactions established within the MDS immune microenvironment between immune and stromal cells. Aims: Recent studies on MDS BM ecosystem suggest a possible symbiotic relationship between cancer, immune and stromal cells. Our project thus aims to underpin the influence of the pathological MSC from MDS BM over NK cells to create a leukemia-permissive microenvironment allowing disease development and progression. Methods: We performed an extensive in vitro characterization of the NK and MSC interactions by co-culture system. Healthy donor (HD) NK cells were co-cultured either with MSC isolated from HD or MDS patient BM samples and were analyzed by high-parametric flow-cytometry, qRT-PCR, secretome and imaging assays. Results: Analyses of supernatants from MSC/NK co-cultures unveiled altered secretion of soluble factors related to inflammation and BM homing such as IL6, CCL2 and CXCL10 in the pathologic condition compared to the healthy one. MDS MSC did not support efficiently NK-cell viability. Moreover, NK cells cultured with MDS MSC were less efficient at eliminating cancer cells compared to NK cells cultured with HD MSC. Finally, metabolic analyses uncovered an altered NK cell energetic profile dictated by the different MSC that could contribute to their poor survival and reduced cytolytic function. Summary/Conclusion: Altogether, our results suggest that MSC from MDS BM edit NK cells to promote an immunosuppressive environment facilitating MDS escape and progression. Further analyses are ongoing to underpin the pivotal role of immune-microenvironment interactions in the treatment response. We expect this study to identify new biomarkers to forecast disease progression and open an avenue for new combination therapies targeting the tumour microenvironment.