IL-15 enhanced antibody-dependent cellular cytotoxicity mediated by NK cells and macrophages
- Zhang, Meili 34
- Wen, Bernard 3
- Anton, Olga M. 3
- Yao, Zhengsheng 5
- Dubois, Sigrid 3
- Ju, Wei 3
- Sato, Noriko 1
- DiLillo, David J. 2
- Bamford, Richard N. 6
-
Ravetch, Jeffrey V.
2
- Waldmann, Thomas A. 3
- 1 Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
- 2 Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065;
- 3 Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
- 4 Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick, MD 21702;
- 5 Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892;
- 6 Transponics, Essex Junction, VT 05452
ISSN: 0027-8424, 1091-6490
Año de publicación: 2018
Volumen: 115
Número: 46
Tipo: Artículo
Otras publicaciones en: Proceedings of the National Academy of Sciences
Resumen
The goal of cancer immunotherapy is to stimulate the host immune system to attack malignant cells. Antibody-dependent cellular cytotoxicity (ADCC) is a pivotal mechanism of antitumor action of clinically employed antitumor antibodies. IL-15 administered to patients with metastatic malignancy by continuous i.v. infusion at 2 μg/kg/d for 10 days was associated with a 38-fold increase in the number and activation status of circulating natural killer (NK) cells and activation of macrophages which together are ADCC effectors. We investigated combination therapy of IL-15 with rituximab in a syngeneic mouse model of lymphoma transfected with human CD20 and with alemtuzumab (Campath-1H) in a xenograft model of human adult T cell leukemia (ATL). IL-15 greatly enhanced the therapeutic efficacy of both rituximab and alemtuzumab in tumor models. The additivity/synergy was shown to be associated with augmented ADCC. Both NK cells and macrophages were critical elements in the chain of interacting effectors involved in optimal therapeutic responses mediated by rituximab with IL-15. We provide evidence supporting the hypothesis that NK cells interact with macrophages to augment the NK-cell activation and expression of FcγRIV and the capacity of these cells to become effectors of ADCC. The present study supports clinical trials of IL-15 combined with tumor-directed monoclonal antibodies.
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