Stimulation of NOD2 in Acute Myeloid Leukemia activates Natural Killer Cells and improves survival

Acute Myeloid Leukemia (AML) is a hematological malignancy of the myeloid lineage of immune cells in the blood and bone marrow. It is characterized by low five-year survival rates of 27.4%, and high incidence of relapse, indicating a need for novel therapeutic strategies. A signature of AML is the evasion of immune surveillance by Natural Killer (NK) cells, which are immune cells possessing anti-leukemic capabilities. NK cell activating receptors are downregulated in AML-NK cells, and these cells exhibit defective cytotoxic ability. Recently, our lab has found that treatment with MTP-PE (a synthetic ligand for NOD2 used for the treatment of osteosarcoma) along with IFNγ provided a survival benefit in a murine model of AML. Data from this study show that blood-derived NK cells isolated from mice treated with MTP-PE and IFNγ show greater levels of maturation, as indicated by markers CD27 and CD11b. Additionally, we saw increased expression of activation/degranulation markers, CD69 and CD107a, on healthy donor NK cells in in vitro cocultures with AML patient samples. This study is focused on elucidating the mechanism by which NK cell activation occurs when AML is treated with MTP-PE and IFNγ. Preliminary data suggests that ligand-receptor cell-to-cell contact between AML cells and NK cells is necessary to elicit the observed NK cell activation. In this study, we show that MTP/IFNγ treated AML cells strongly upregulate IL-15, an important cytokine involved in NK cell expansion and activation, as well as ligands of the receptor NKG2D. In AML patient samples, we have found the co-treatment to upregulate CD69 and CD107a on suppressed patient NK cells, both in peripheral blood and apheresis. We also observed expansion of NK cells in these patient samples. Further study is necessary to evaluate and understand the potential of MTP-PE and IFNγ to activate suppressed NK cells in Acute Myeloid Leukemia and improve anti-leukemic immunosurveillance.Pelotonia Undergraduate Research FellowshipNo embargoAcademic Major: Biomedical Scienc