A VEGFR-3 Antagonist Increases IFN-γ Expression on Low Functioning NK Cells in Acute Myeloid Leukemia

Abstract

Although the importance of vascular endothelial growth factor receptor (VEGFR)-3 has been demonstrated in acute myeloid leukemia (AML), the role of VEGFR-3 in functioning natural killer (NK) cells remains largely unexplored. NK cells can destroy cancer cells by releasing the cytokine interferon (IFN)-γ, but NK cells in AML patients (AML NK cells) have low cytolytic activity. In the present study, we investigated whether lymphatic markers including VEGFR-3 are expressed on low-functioning AML NK cells and VEGFR-3 antagonist can restore expression of IFN-γ in NK cells. Samples from 67 de novo AML patients and 34 healthy donors were analyzed for lymphatic markers expression using RT-PCR, flow cytometry, and immunostaining. For the cytotoxicity assays, K562 cells and AML NK cells were used as target and effector cells, respectively. To block VEGFR-3, MAZ51 was added to NK cells, which were then subjected to FACS analysis. Compared with NK cells from healthy donors (healthy NK cells), AML NK cells exhibited higher levels of VEGFR-3 and lower expression of IFN-γ. VEGFR-3-expressing AML NK cells were less potent than healthy NK cells in terms of killing K562 cells. The level of IFN-γ in AML NK cells was increased by VEGFR-3 antagonist treatment, indicating the functional relevance of VEGFR-3 in IFN-γ-secreting NK cells. Collectively, our data suggest a relationship between VEGFR-3 and IFN-γ expression in NK cells and raise the possibility of advanced therapeutic approaches involving VEGFR-3 antagonist treatment prior to NK immune cell therapy in AML.