Up-regulation of NK cell activating receptors following allogeneic hematopoietic stem cell transplantation under a lymphodepleting reduced intensity regimen is associated with elevated IL-15 levels.
Because natural killer (NK) cells can be potent anti-tumor effectors after allogeneic stem cell transplantation, we investigated NK reconstitution and receptor expression in patients undergoing allogeneic hematopoietic stem cell transplantation, focusing on the activating receptors that trigger anti-tumor responses. We determined that NK levels in the peri-transplant period were inversely proportional to the dramatic rise and fall in plasma levels of the NK homeostatic cytokine IL-15, which increased more than 50-fold from pretreatment to the day of transplant during the lymphoreductive preparative regimen. Furthermore, in NK cells cultured with IL-15, we observed an up-regulation of the activating receptors NKG2D, NKp30, and NKp46, associated with an increase in anti-tumor lytic activity. Similarly, the expression of these activating receptors increased significantly during the early post-transplant period, concurrent with a rapid increase in total NK cells and a shift toward increased expression of CD56. These data suggest that the cytokine milieu of transplants, in particular elevated levels of IL-15, may contribute to anti-tumor efficacy post-transplant by enhancing the recovery of NK subsets and modulating expression of activating receptors.
Boyiadzis
Michael
M
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. boyiadzism@upmc.edu
Memon
Sarfraz
S
Carson
Jesse
J
Allen
Kenton
K
Szczepanski
Miroslaw J
MJ
Vance
Barbara A
BA
Dean
Robert
R
Bishop
Michael R
MR
Gress
Ronald E
RE
Hakim
Frances T
FT
D000328:Adult; D000368:Aged; D019002:CD56 Antigen / Q000096:biosynthesis / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D020544:Graft vs Leukemia Effect / Q000187:drug effects / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D019409:Interleukin-15 / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008212:Lymphocyte Depletion; D008232:Lymphoproliferative Disorders / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D055728:Primary Myelofibrosis / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D019002:CD56 Antigen; D019409:Interleukin-15; C527085:KLRK1 protein, human; C112260:NCR1 protein, human; C431710:NCR3 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell