NK-cell purging of leukemia: superior antitumor effects of NK cells H2 allogeneic to the tumor and augmentation with inhibitory receptor blockade.
Natural killer (NK) cells are composed of subsets characterized by the expression of inhibitory or activating receptors, or both, specific for different major histocompatibility complex (MHC) class I determinants. We have previously shown that inhibitory receptor blockade of syngeneic NK cells was an effective means of ex vivo purging of leukemia-contaminated bone marrow and that the transplantation of mice with the purged bone marrow cells (BMCs) resulted in long-term, relapse-free survival. We have extended the investigation to assess the antitumor effects mediated by NK cells H2-allogeneic to tumor cells. We demonstrate that various tumor cell lines are more susceptible to lysis by H2-allogeneic NK cells than by syngeneic NK cells in vitro even though comparable percentages of Ly49 NK cells were present. Using allogeneic NK cells to purge leukemia-contaminating BMCs before transplantation resulted in a higher proportion of mice with long-term survival than using syngeneic NK cells. Allogeneic NK cells did not suppress hematopoietic reconstitution as measured by granulocyte/monocyte-colony-forming unit (CFU-GM), complete blood count (CBC), and donor chimerism at various days after transplantation. Inhibitory receptor blockade of allogeneic NK cells also significantly increased these antitumor effects at lower NK/tumor ratios compared with those of syngeneic NK cells. These results demonstrate that H2-allogeneic NK cells mediate more potent antitumor effects than syngeneic NK cells without adverse hematologic effects and thus may be useful in cancer therapy.
Koh
Crystal Y
CY
Department of Microbiology and Immunology, University of Nevada School of Medicine, Applied Research Facility, Bldg 344/MS 199, Reno, NV 89557, USA.
Ortaldo
John R
JR
Blazar
Bruce R
BR
Bennett
Michael
M
Murphy
William J
WJ
D000818:Animals; D016465:Bone Marrow Purging / Q000379:methods*; D016026:Bone Marrow Transplantation / Q000379:methods; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D020544:Graft vs Leukemia Effect; D006183:H-2 Antigens / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D054340:Receptors, KIR; D015996:Survival Rate; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D006183:H-2 Antigens; D011971:Receptors, Immunologic; D054340:Receptors, KIR