FLT3 ligand administration after hematopoietic cell transplantation increases circulating dendritic cell precursors that can be activated by CpG oligodeoxynucleotides to enhance T-cell and natural killer cell function.
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.
Chen
Wei
W
University of Minnesota Cancer Center, Minneapolis, Minnesota 5455, USA. chenw@umn.edu
Chan
Anissa S H
AS
Dawson
Amanda J
AJ
Liang
Xueqing
X
Blazar
Bruce R
BR
Miller
Jeffrey S
JS
D000328:Adult; D017951:Antigen Presentation; D001772:Blood Cell Count; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy; D002454:Cell Differentiation / Q000187:drug effects; D018899:CpG Islands; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000502:physiology; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; C084881:flt3 ligand protein