title: Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: utilization for ovarian cancer treatment.
abstract: Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L) has been considered to be a major route of delivery for tumor immunotherapy because expression of its receptor, FLT3, was detected predominantly in hematopoetic progenitor cells. However, several studies indicate that FLT3L locally overexpressed in tumor or dendritic cells (DCs) also shows an anti-tumor effect. In the current study, we found that FLT3 expression is not present in monocytes but is instead induced in DCs through the differentiation process resulting from stimulation by GM-CSF and IL-4. Addition of FLT3L further augmented FLT3 induction and also increased CD40 expression in DCs, leading to enhanced induction of lymphoblastoid cell line-targeted cytotoxic T-lymphocyte response and CD107a mobilization in CD8+ T cells. Furthermore, FLT3L also induced FLT3 expression in peripheral blood NK cells that showed an enhanced response detected by CD107a mobilization. In a murine ovarian cancer model, locally expressed FLT3L showed anti-tumor effects. Collectively, the current study indicates that FLT3L has an immunostimulatory effect on peripheral blood cells and FLT3L targeted to mature peripheral blood cells may serve as a useful tool for cancer immunotherapy.
authors.affiliation: Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Noriomi
authors.initials: N
authors.lastname: Matsumura
authors.forename: Masaki
authors.initials: M
authors.lastname: Mandai
authors.forename: Junzo
authors.initials: J
authors.lastname: Hamanishi
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Fukuhara
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yagi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Higuchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Takakura
authors.forename: Shingo
authors.initials: S
authors.lastname: Fujii
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism; D019002:CD56 Antigen / Q000032:analysis; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000276:immunology; D010051:Ovarian Neoplasms / Q000628:therapy*; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D019002:CD56 Antigen; D008024:Ligands; D052118:Lysosomal-Associated Membrane Protein 1; D008565:Membrane Proteins; C084881:flt3 ligand protein; D051941:fms-Like Tyrosine Kinase 3