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

Michel van Gelder*, Ariane Vanclee, Catharina H. M. J. van Elssen, Pierre Hupperets, Lotte Wieten, Gerard M. Bos

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Web of Science)

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 2x 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.

Original languageEnglish
Pages (from-to)421-433
Number of pages13
JournalBreast Cancer Research and Treatment
Volume161
Issue number3
DOIs
Publication statusPublished - Feb 2017

Keywords

  • 4T1
  • Breast cancer
  • Immunotherapy
  • Alloreactive NK cell
  • Hematopoietic stem cell transplantation
  • KIR-LIGAND INCOMPATIBILITY
  • VERSUS-LEUKEMIA ACTIVITY
  • ACUTE MYELOID-LEUKEMIA
  • MHC CLASS-I
  • T-CELLS
  • TUMOR-CELLS
  • ADOPTIVE IMMUNOTHERAPY
  • ACTIVATING RECEPTORS
  • HEMATOPOIETIC SCT
  • SUPPRESSOR-CELLS

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