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Breast Cancer Res Treat. 2017 Feb;161(3):421-433. doi: 10.1007/s10549-016-4067-6. Epub 2016 Dec 3.

Bone marrow produces sufficient alloreactive natural killer (NK) cells in vivo to cure mice from subcutaneously and intravascularly injected 4T1 breast cancer.

Author information

1
Department of Internal Medicine, Maastricht University Medical Center, Postbus 5800, 6202 AZ, Maastricht, The Netherlands. m.van.gelder@mumc.nl.
2
Department of Internal Medicine, Maastricht University Medical Center, Postbus 5800, 6202 AZ, Maastricht, The Netherlands.
3
Department of Transplantation Immunology, Maastricht University Medical Center, Postbus 5800, 6202 AZ, Maastricht, The Netherlands.

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

4T1; Alloreactive NK cell; Breast cancer; Hematopoietic stem cell transplantation; Immunotherapy

PMID:
27915436
PMCID:
PMC5241334
DOI:
10.1007/s10549-016-4067-6
[Indexed for MEDLINE]
Free PMC Article

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