Antibody-dependent cell lysis by NK cells is preserved after sarcoma-induced inhibition of NK cell cytotoxicity
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ORIGINAL ARTICLE
Antibody-dependent cell lysis by NK cells is preserved after sarcoma-induced inhibition of NK cell cytotoxicity Jens H. W. Pahl • S. Eriaty N. Ruslan • Kitty M. C. Kwappenberg Monique M. van Ostaijen-ten Dam • Maarten J. D. van Tol • Arjan C. Lankester • Marco W. Schilham
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Received: 28 August 2012 / Accepted: 13 February 2013 / Published online: 27 April 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract 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-b. 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 FccRIIIa/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
Electronic supplementary material The online version of this article (doi:10.1007/s00262-013-1406-x) contains supplementary material, which is available to authorized users. J. H. W. Pahl S. E. N. Ruslan K. M. C. Kwappenberg M. M. van Ostaijen-ten Dam M. J. D. van Tol A. C. Lankester Department of Pediatrics, Leiden University Medical Centre, Leiden, The Netherlands e-mail: [email protected] M. W. Schilham (&) Department of Pediatrics, Laboratory for Immunology, P3-P, Leiden University Medical Centre, Albinusdreef 2, 2333ZA Leiden, The Netherlands e-mail: [email protected]
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. Keywords
NK cell NKG2D ADCC IL15 Sarcoma
Introduction Osteosarcoma and Ewing’s sarcoma represent the most frequent osseous, malignant tumors in adolescents and young adults. The current treatment consists of a combination of systemic multi-drug chemotherapy and surgical resection [1–3]. Up to 70 % of patients with localized disease achieve persistent remission. In contrast, the prognosis of patients with metastasized and recurrent disease has remained dismal, despite advancements in surgical techniques
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