Myeloid-Derived Suppressor Phenotype of Leukemic Blasts in Association with Increased Suppressor T Cell Subsets in Acute Myelogenous Leukemia– Evidence for Immunoediting.

Abstract 2528

The quantitative lymphocyte recovery after remission induction is known to correlate with the outcome of the patients with acute myeloid leukemia (AML), suggesting the immune-surveillance is at least partly responsible for maintained remissions. However defects in lymphocyte function and increased regulatory T cell numbers suggest a permissive immune environment for leukemia cell growth. Understanding the interplay between the leukemia and the immune system may provide insight into the mechanisms governing leukemia cure or relapse after induction chemotherapy and lead to better remission treatments to prevent relapse. To look for evidence of immune escape and possible immunoediting of lymphocyte function by the leukemia, we undertook an extensive phenotypic characterization of lymphocytes and AML blasts in blood and marrow at presentation, through remission to full hematological recovery.

Twenty patients (mean age 57 years; range 31–69) with newly diagnosed AML were enrolled in a protocol permitting blood and marrow collection for investigational purposes (VICCHEM 1073). Mononuclear cells were obtained from blood and marrow samples collected at onset, 14–21 days and 28–35 days after start of induction chemotherapy. Mononuclear cells were analyzed for lymphocyte phenotyping by flow cytometry and subset frequencies were compared with 5 healthy controls (mean age 31). Leukemic blast cells (Lineage CD2/3/19 negative, CD45+ cells) were characterized in blood and marrow. T cells showed several, largely persisting, abnormalities: (1) A decrease in central memory CD197+, CD27+, CD45RO+ CD8+ (p=0.03) and CD4+ T cells (p=0.1) in the blood at presentation with a corresponding decrease in CD197+CD27+ CD45RO-naïve subsets (2) A significant increase in PD1+ high expression suppressor phenotype for CD8+ (p=0.001) and CD4+ (p=0.01) cells at recovery (days 28–35). (3) At presentation FoxP3+ CD4+ regulatory T cells (T_reg) were increased significantly at presentation (p=0.03) and remained elevated. This increase was due mainly to augmentation in the Helios^loFoxP3^hi induced T_reg (p=0.04) and CD45RA^loFoxP3^hi effector T_reg fraction (p=0.002). These changes persisted into remission. The leukemic blast population included a variable population of cells with the CD11b⁺CD124⁺HLA-DR^lo myeloid derived suppressor (MDSC) phenotype. The frequency of MDSC was higher in bone marrow (median 6.1% vs 3.1% in blood; p=0.44) and a significantly higher proportion of marrow MDSC expressed the lymphocyte suppressor molecule PDL-1 (54.5% vs 28.5%; p=0.0189). NK cell subsets showed significantly lower frequencies of immature CD56^bright NK cells (p=0.02), and correspondingly decreased more mature CD56^dim CD57-KIR-NKG2A+ subsets at presentation (p=0.039). NK cell subsets trend to recover during remission but with reduced frequency of mature CD57+, KIR+ CD56^dim NK cells in recovery (p=0.018).

This study confirms the occurrence of significant alterations in T cell phenotype associated with increased regulatory and suppressor phenotype. The occurrence of the MDSC phenotype within the leukemia blast population suggests that myeloid leukemia cells promote a permissive immune environment for leukemia growth and persistence through immunoediting. These changes as well as abnormalities in NK cells tend to persist into remission and may contribute to leukemic relapse.

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