title: Bone marrow produces sufficient alloreactive natural killer (NK) cells in vivo to cure mice from subcutaneously and intravascularly injected 4T1 breast cancer.
abstract: Administration of 5 million alloreactive natural killer (NK) cells after low-dose chemo-irradiation cured mice of 4T1 breast cancer, supposedly dose dependent. We now explored the efficacy of bone marrow as alternative in vivo source of NK cells for anti-breast cancer treatment, as methods for in vitro clinical scale NK cell expansion are still in developmental phases.
  
  
  
  Progression-free survival (PFS) after treatment with different doses of spleen-derived alloreactive NK cells to 4T1-bearing Balb/c mice was measured to determine a dose-response relation. The potential of bone marrow as source of alloreactive NK cells was explored using MHC-mismatched mice as recipients of 4T1. Chemo-irradiation consisted of 2× 2 Gy total body irradiation and 200 mg/kg cyclophosphamide. Antibody-mediated in vivo NK cell depletion was applied to demonstrate the NK cell's role.
  
  
  
  Administration of 2.5 instead of 5 million alloreactive NK cells significantly reduced PFS, evidencing dose responsiveness. Compared to MHC-matched receivers of subcutaneous 4T1, fewer MHC-mismatched mice developed tumors, which was due to NK cell alloreactivity because in vivo NK cell depletion facilitated tumor growth. Application of low-dose chemo-irradiation increased plasma levels of NK cell-activating cytokines, NK cell activity and enhanced NK cell-dependent elimination of subcutaneous tumors. Intravenously injected 4T1 was eliminated by alloreactive NK cells in MHC-mismatched recipients without the need for chemo-irradiation.
  
  
  
  Bone marrow is a suitable source of sufficient alloreactive NK cells for the cure of 4T1 breast cancer. These results prompt clinical exploration of bone marrow transplantation from NK-alloreactive MHC-mismatched donors in patients with metastasized breast cancer.
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Postbus 5800, 6202 AZ, Maastricht, The Netherlands. m.van.gelder@mumc.nl.
authors.forename: Michel
authors.identifier: 0000-0001-8698-4351
authors.initials: M
authors.lastname: van Gelder
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Postbus 5800, 6202 AZ, Maastricht, The Netherlands.
authors.forename: Ariane
authors.initials: A
authors.lastname: Vanclée
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Postbus 5800, 6202 AZ, Maastricht, The Netherlands.
authors.forename: Catharina H M J
authors.initials: CH
authors.lastname: van Elssen
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Postbus 5800, 6202 AZ, Maastricht, The Netherlands.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hupperets
authors.affiliation: Department of Transplantation Immunology, Maastricht University Medical Center, Postbus 5800, 6202 AZ, Maastricht, The Netherlands.
authors.forename: Lotte
authors.initials: L
authors.lastname: Wieten
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Postbus 5800, 6202 AZ, Maastricht, The Netherlands.
authors.forename: Gerard M
authors.initials: GM
authors.lastname: Bos
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation
chemical_list: D016207:Cytokines
keywords: 4T1; Alloreactive NK cell; Breast cancer; Hematopoietic stem cell transplantation; Immunotherapy