PB1881 EVALUATION OF THE QUANTITATIVE CHARACTERISTICS OF MYELOID DERIVED SUPPRESSOR CELLS IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AND ASSOCIATED HYPOGAMMAGLOBULINEMIA

Background: Myeloid Derived Suppressor Cells (MDSCs) are immature myeloid cells with immunosuppressive properties implicated in chronic inflammation and tumor progression. They are divided in two cell fractions, the polymorphonuclear (PMN)‐MDSCs and the monocytic (M)‐MDSCs, characterized by the immunophenotype HLA‐DR low/‐ CD11b + CD33 + CD15 + and HLA‐DR low/‐ CD11b + CD33 + CD14 + , respectively. The immunosuppressive function of MDSCs is mainly mediated by activation of arginase‐1 and nitric oxide synthase 2, production of reactive oxygen species, modulation of macrophage polarization and induction of T‐regulatory cells. The above mechanisms result in reduction and inactivation of T‐cells and inability of B‐cell activation. Aims: Chronic lymphocytic leukemia (CLL) is frequently associated with hypogammaglobulinemia predisposing patients to infections. No conclusive evidence on the correlation between the immunoglobulin (Ig) levels and the normal B‐cell reserves has been documented and, overall, the underlying mechanisms implicated in the Ig defect remain unclear. The aim of the study is to investigate the possible involvement of MDSCs in CLL‐associated hypogammaglobulinemia by evaluating the proportion of peripheral blood (PB) PMN‐MDSCs and M‐MDSCs in CLL patients. Methods: We have studied 50 patients with CLL and 15 age‐ and sex‐matched healthy subjects. None of the patients was receiving any treatment for the disease. We evaluated the proportion of PMN‐MDSCs and M‐MDSCs by flow cytometry in the low density fraction of the PB mononuclear cells following Ficoll gradient centrifugation according to previously reported data (Bronte et al , Nat Commun 2016). Results: The proportion of PMN‐MDSCs and M‐MDSCs was significantly higher in CLL patients (1.63% ± 1.68%, median 1.03% and 1.33% ± 1.36%, median 0.88%, respectively) compared to healthy subjects (0.11% ± 0.23%, median 0.01% and 0.61% ± 0.51%, median 0.52%, respectively) (P < 0.0001 and P = 0.0455, respectively). Patients were further divided in two groups, those with normal Ig levels (n = 31; Stage A:28, Stage B:1, Stage C:2) and those with low levels of at least one Ig class (n = 19; Stage A:14, Stage B:4, Stage C:1). Both patient groups, namely those with normal and those with low Ig levels, displayed significantly increased proportion of PMN‐MDSCs (1.56% ± 1.52%, median 1.04% and 1.73% ± 1.94%, median 0.90%, respectively) compared to healthy subjects (P < 0.0001 and P < 0.0001, respectively). As regards to M‐MDSCs, patients with normal Ig levels displayed increased proportion of this cell population (1.35% ± 1.37%, median 0.98%) compared to healthy controls (P = 0.0106) whereas patients with low Ig displayed also increased proportion of these cells (1.28% ± 1.38%, median 0.71%) but not at a statistically significant level compared to controls. No statistically significant difference was found in the proportion of PMN‐MDSCs and M‐MDSs between patients with normal or low Ig levels. Summary/Conclusion: CLL patients display increased proportion of PB PMN‐MDSCs and M‐MDSCs compared to healthy individuals. This abnormality occurs in patients with normal and low Ig levels without significant differences, suggesting that MDSCs’ expansion does not represent the main pathogenetic mechanism for the Ig defect in CLL. We are currently investigating the T‐cell suppressive effects of MDSCs looking for potential differences between patients with normal and low Ig levels. Our results contribute to the few available evidence implicating MDSCs in CLL and highlight their emerging role as new biomarkers in the disease.