Antibody-dependent cell lysis by NK cells is preserved after sarcoma-induced inhibition of NK cell cytotoxicity

• Published in: Cancer Immunology, Immunotherapy Vol. 62; no. 7; pp. 1235 - 1247
• Main Authors: Pahl, Jens H. W., Ruslan, S. Eriaty N., Kwappenberg, Kitty M. C., van Ostaijen-ten Dam, Monique M., van Tol, Maarten J. D., Lankester, Arjan C., Schilham, Marco W.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2013; Springer Nature B.V
• Subjects: Antibodies; Antibody-Dependent Cell Cytotoxicity; Antigens, Differentiation, T-Lymphocyte - biosynthesis; Bone cancer; Cancer Research; Cell Line, Tumor; Cells; Chemotherapy; Coculture Techniques; Cytotoxicity; Cytotoxicity, Immunologic; Ewings sarcoma; Humans; Immunology; Immunotherapy; Interleukin-15 - immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Ligands; Lymphocyte Activation; Lymphocytes; Medicine; Medicine & Public Health; Natural Cytotoxicity Triggering Receptor 3 - biosynthesis; NK Cell Lectin-Like Receptor Subfamily K - biosynthesis; Oncology; Original; Original Article; Osteosarcoma - immunology; Pediatrics; Penicillin; Receptors, IgG - biosynthesis; Receptors, Natural Killer Cell; Sarcoma, Ewing - immunology; Transforming Growth Factor beta - immunology; Tumors; United States > US; NKG2D; Sarcoma; IL15; ADCC; NK cell
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-013-1406-x

Osteosarcoma and Ewing’s sarcoma tumor cells are susceptible to IL15-induced or antibody-mediated cytolytic activity of NK cells in short-term cytotoxicity assays. When encountering the tumor environment in vivo, NK cells may be in contact with tumor cells for a prolonged time period. We explored whether a prolonged interaction with sarcoma cells can modulate the activation and cytotoxic activity of NK cells. The 40 h coculture of NK cells with sarcoma cells reversibly interfered with the IL15-induced expression of NKG2D, DNAM-1 and NKp30 and inhibited the cytolytic activity of NK cells. The inhibitory effects on receptor expression required physical contact between NK cells and sarcoma cells and were independent of TGF-β. Five days pre-incubation of NK cells with IL15 prevented the down-regulation of NKG2D and cytolytic activity in subsequent cocultures with sarcoma cells. NK cell FcγRIIIa/CD16 receptor expression and antibody-mediated cytotoxicity were not affected after the coculture. Inhibition of NK cell cytotoxicity was directly linked to the down-regulation of the respective NK cell-activating receptors. Our data demonstrate that the inhibitory effects of sarcoma cells on the cytolytic activity of NK cells do not affect the antibody-dependent cytotoxicity and can be prevented by pre-activation of NK cells with IL15. Thus, the combination of cytokine-activated NK cells and monoclonal antibody therapy may be required to improve tumor targeting and NK cell functionality in the tumor environment.