Th163 - Restoring Natural Killer Cells with FLT4-targeting Peptide in Acute Myeloid Leukemia

Abstract Text: The Fms-related tyrosine kinase-4 (FLT4) is involved in AML progression. Previously, we found that dysfunctional natural killer (NK) cells with low interferon-gamma (IFN-γ) in AML are restored by FLT4 antagonist, MAZ51. However, peptides targeting FLT4 in restoring NK cells in AML are not elucidated. We developed peptides targeting FLT4 for clinical application and ultimately selected several peptides to examine whether the frequency of lymphocytes, especially T cells and NK cells, and high expression of IFN-γ were restored by peptide treatments, as shown by MAZ51 treatment in AML syngeneic mouse model. Through in vivo experiments, MAZ51, peptide, and cytosine arabinoside (ara-C) were treated. Flow cytometry, elispot assay, and real-time qPCR analysis were performed. Similar with MAZ51, high IFN-γ was expressed in AML-NK cells when using the specific peptide. In addition, T and NK cells can be restored with high IFN-γ in leukemic environment, when peptide was co-cultured with ara-C. Interestingly, the frequency of regulatory T cells significantly decreased by peptide, implying the role of peptide in modulating the AML-related immune niche. When peptide was combined with ara-C, the spleen and liver taken from AML mice showed more effective eradication of AML blasts than single therapy. Based on the results of NK cells’ functional recovery by FLT4 inhibitory peptide in AML mice, peptide targeting FLT4 in combination with chemotherapy may inhibit AML progression by blocking the lymphatic markers on AML NK cells. These findings possibly provide some clues for developing a novel immunotherapeutic strategy for standard therapy-resistant patients with AML in clinic.