Tags

Type your tag names separated by a space and hit enter

NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways.
Mol Immunol. 2008 Sep; 45(15):3917-25.MI

Abstract

INTRODUCTION

Ewing sarcoma (EWS) is a malignant bone-associated sarcoma, with poor prognosis in case of metastasis or relapse. To explore the feasibility of natural killer (NK) cell mediated immunotherapy and to identify molecular mechanisms involved, the susceptibility of EWS to NK cells was investigated.

METHODS AND RESULTS

All EWS cell lines tested (n=7) were lysed by purified allogeneic NK cells from healthy donors, and the efficacy of lysis was increased by activating NK cells with interleukin-15 (IL-15). FACS analysis and immunohistochemistry revealed that EWS cell lines as well as primary tumor cells expressed ligands for the activating NK cell receptors NKG2D and DNAM-1. NK cell cytotoxicity to EWS cells critically depended on the combination of NKG2D and DNAM-1 signaling, since blocking either of these receptors abrogated lysis by resting NK cells. Cytokine-activated NK cells more efficiently recognized EWS cells, since only combined, but not single blockade of NKG2D and DNAM-1 by antibodies inhibited lysis of EWS cells. Induction or blockade of HLA class I on EWS cells did not significantly influence lysis. This suggests that predominantly activating, rather than inhibitory signals on EWS cells determined susceptibility to NK cell cytotoxicity. NK cell cytotoxicity to EWS cells and K562 was reduced in EWS patients at diagnosis (n=11) compared to age matched controls, despite normal NK cell numbers and increased expression of NKG2D. The impaired function of these NK cells was restored after activation with IL-15 in vitro.

CONCLUSION

These results demonstrate that EWS cells are potentially susceptible to NK cell cytotoxicity due to the expression of activating NK cell receptor ligands. The use of cytokine-activated NK cells rather than resting NK cells in immunotherapy may be instrumental to optimize NK cell reactivity to EWS.

Authors+Show Affiliations

Division of Immunology, Hematology, Oncology, Bone Marrow Transplantation and Autoimmune Diseases, Department of Pediatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18657862

Citation

Verhoeven, Dirk H J., et al. "NK Cells Recognize and Lyse Ewing Sarcoma Cells Through NKG2D and DNAM-1 Receptor Dependent Pathways." Molecular Immunology, vol. 45, no. 15, 2008, pp. 3917-25.
Verhoeven DH, de Hooge AS, Mooiman EC, et al. NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways. Mol Immunol. 2008;45(15):3917-25.
Verhoeven, D. H., de Hooge, A. S., Mooiman, E. C., Santos, S. J., ten Dam, M. M., Gelderblom, H., Melief, C. J., Hogendoorn, P. C., Egeler, R. M., van Tol, M. J., Schilham, M. W., & Lankester, A. C. (2008). NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways. Molecular Immunology, 45(15), 3917-25. https://doi.org/10.1016/j.molimm.2008.06.016
Verhoeven DH, et al. NK Cells Recognize and Lyse Ewing Sarcoma Cells Through NKG2D and DNAM-1 Receptor Dependent Pathways. Mol Immunol. 2008;45(15):3917-25. PubMed PMID: 18657862.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways. AU - Verhoeven,Dirk H J, AU - de Hooge,Alfons S K, AU - Mooiman,Esther C K, AU - Santos,Susy Justo, AU - ten Dam,Monique M, AU - Gelderblom,Hans, AU - Melief,Cornelis J M, AU - Hogendoorn,Pancras C W, AU - Egeler,R Maarten, AU - van Tol,Maarten J D, AU - Schilham,Marco W, AU - Lankester,Arjan C, Y1 - 2008/07/26/ PY - 2008/05/17/received PY - 2008/06/16/revised PY - 2008/06/19/accepted PY - 2008/7/29/pubmed PY - 2008/12/17/medline PY - 2008/7/29/entrez SP - 3917 EP - 25 JF - Molecular immunology JO - Mol. Immunol. VL - 45 IS - 15 N2 - INTRODUCTION: Ewing sarcoma (EWS) is a malignant bone-associated sarcoma, with poor prognosis in case of metastasis or relapse. To explore the feasibility of natural killer (NK) cell mediated immunotherapy and to identify molecular mechanisms involved, the susceptibility of EWS to NK cells was investigated. METHODS AND RESULTS: All EWS cell lines tested (n=7) were lysed by purified allogeneic NK cells from healthy donors, and the efficacy of lysis was increased by activating NK cells with interleukin-15 (IL-15). FACS analysis and immunohistochemistry revealed that EWS cell lines as well as primary tumor cells expressed ligands for the activating NK cell receptors NKG2D and DNAM-1. NK cell cytotoxicity to EWS cells critically depended on the combination of NKG2D and DNAM-1 signaling, since blocking either of these receptors abrogated lysis by resting NK cells. Cytokine-activated NK cells more efficiently recognized EWS cells, since only combined, but not single blockade of NKG2D and DNAM-1 by antibodies inhibited lysis of EWS cells. Induction or blockade of HLA class I on EWS cells did not significantly influence lysis. This suggests that predominantly activating, rather than inhibitory signals on EWS cells determined susceptibility to NK cell cytotoxicity. NK cell cytotoxicity to EWS cells and K562 was reduced in EWS patients at diagnosis (n=11) compared to age matched controls, despite normal NK cell numbers and increased expression of NKG2D. The impaired function of these NK cells was restored after activation with IL-15 in vitro. CONCLUSION: These results demonstrate that EWS cells are potentially susceptible to NK cell cytotoxicity due to the expression of activating NK cell receptor ligands. The use of cytokine-activated NK cells rather than resting NK cells in immunotherapy may be instrumental to optimize NK cell reactivity to EWS. SN - 0161-5890 UR - https://www.unboundmedicine.com/medline/citation/18657862/NK_cells_recognize_and_lyse_Ewing_sarcoma_cells_through_NKG2D_and_DNAM_1_receptor_dependent_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0161-5890(08)00255-1 DB - PRIME DP - Unbound Medicine ER -