NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs.
NKT cells have pivotal roles in immune regulation and tumor immunosurveillance. We report that the G-CSF and FMS-like tyrosine kinase 3 ligand (Flt-3L) chimeric cytokine, progenipoietin-1, markedly expands the splenic and hepatic NKT cell population and enhances functional responses to alpha-galactosylceramide. In a murine model of allogeneic stem cell transplantation, donor NKT cells promoted host DC activation and enhanced perforin-restricted CD8+ T cell cytotoxicity against host-type antigens. Following leukemic challenge, donor treatment with progenipoietin-1 significantly improved overall survival when compared with G-CSF or control, attributable to reduced graft-versus-host disease mortality and paradoxical augmentation of graft-versus-leukemia (GVL) effects. Enhanced cellular cytotoxicity was dependent on donor NKT cells, and leukemia clearance was profoundly impaired in recipients of NKT cell-deficient grafts. Enhanced cytotoxicity and GVL effects were not associated with Flt-3L signaling or effects on DCs but were reproduced by prolonged G-CSF receptor engagement with pegylated G-CSF. Thus, modified G-CSF signaling during stem cell mobilization augments NKT cell-dependent CD8+ cytotoxicity, effectively separating graft-versus-host disease and GVL and greatly expanding the potential applicability of allogeneic stem cell transplantation for the therapy of malignant disease.
Morris
Edward S
ES
Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
MacDonald
Kelli P A
KP
Rowe
Vanessa
V
Banovic
Tatjana
T
Kuns
Rachel D
RD
Don
Alistair L J
AL
Bofinger
Helen M
HM
Burman
Angela C
AC
Olver
Stuart D
SD
Kienzle
Norbert
N
Porcelli
Steven A
SA
Pellicci
Daniel G
DG
Godfrey
Dale I
DI
Smyth
Mark J
MJ
Hill
Geoffrey R
GR
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000502:physiology; D020544:Graft vs Leukemia Effect / Q000187:drug effects / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000276:immunology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D003115:Colony-Stimulating Factors; D005699:Galactosylceramides; D008565:Membrane Proteins; D011994:Recombinant Proteins; C493154:alpha-galactosylceramide; C084881:flt3 ligand protein; C434603:progenipoietin-1; D016179:Granulocyte Colony-Stimulating Factor