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 language | English |
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Pages (from-to) | 421-433 |
Number of pages | 13 |
Journal | Breast Cancer Research and Treatment |
Volume | 161 |
Issue number | 3 |
DOIs | |
Publication status | Published - 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