Dendritic cells (DCs) are key effectors in innate immunity and play critical roles in triggering adaptive immune responses. FLT3 ligand (FLT3-L) is essential for DC development from hematopoietic progenitors. In a phase I clinical trial, we demonstrated that immunotherapy with subcutaneous injection of FLT3-L is safe and well tolerated in cancer patients recovering from autologous hematopoietic cell transplantation (HCT). FLT3-L administration significantly increased the frequency and absolute number of blood DC precursors without affecting other mature cell lineages during the 6-week course of FLT3-L therapy. After 14 days of FLT3-L administration, the number of blood CD11c+ DCs, plasmacytoid DCs (PDCs), and CD14+ monocytes increased by 5.3-, 2.9-, 3.8-fold, respectively, and was maintained at increased levels throughout FLT3-L therapy. FLT3-L-increased blood DCs in HCT patients were immature and had modest enhancing effects on in vitro T-cell proliferation to antigens and natural killer (NK) cell function. The addition of type B CpG oligodeoxynucleotides (ODNs) to peripheral blood mononuclear cells obtained from HCT patients receiving FLT3-L therapy induced rapid maturation of both CD11c+ DCs and PDCs and enhanced T-cell proliferative responses. In addition, CpG ODN induced potent activation of NK cells from FLT3-L-treated patients with increased surface CD69 expression and augmented cytotoxicity. CpG ODN-induced activation of NK cells was primarily via an indirect mechanism through PDCs. These findings suggest that FLT3-L mobilization of DC precursors followed by a specific DC stimulus such as CpG ODN may provide a novel strategy to manipulate antitumor immunity in patients after HCT.
Bibliographical noteFunding Information:
We gratefully acknowledge Sue Fautsch at the Cancer Center Translational Cell Therapy Core for the collection of research samples and Roby Nicklow for clinical coordination of this research trial. This work was supported in part by research grants from the Randy Shaver Cancer Research and Community Fund; the Children’s Cancer Research Fund and Leukemia Research Fund (W.C.); the Leukemia Task Force and National Institutes of Health grant no. RO1 CA72669 (B.R.B.); and the Fairview-University Medical Center Stem Cell Laboratory (J.S.M). We also acknowledge of the support of the University of Minnesota Bone Marrow Transplantation Research Fund.
- CpG DNA
- Dendritic cells
- FLT3 ligand
- NK cells
- T lymphocytes