TY  - JOUR
A1  - Berghuis, Dagmar
A1  - Schilham, Marco Willem
A1  - Vos, Hanneke I.
A1  - Santos, Susy J.
A1  - Klöß, Stephan
A1  - Buddingh', Emilie P.
A1  - Maarten Egeler, R.
A1  - Hogendoorn, Pancras Cornelis Wilhelmus
A1  - Lankester, Arjan C.
T1  - Histone deacetylase inhibitors enhance expression of NKG2D ligands in Ewing sarcoma and sensitize for natural killer cell-mediated cytolysis
T2  - Clinical Sarcoma Research
N2  - Background: Ewing sarcoma patients have a poor prognosis despite multimodal therapy. Integration of combination immunotherapeutic strategies into first-/second-line regimens represents promising treatment options, particularly for patients with intrinsic or acquired resistance to conventional therapies. We evaluated the susceptibility of Ewing sarcoma to natural killer cell-based combination immunotherapy, by assessing the capacity of histone deacetylase inhibitors to improve immune recognition and sensitize for natural killer cell cytotoxicity.

Methods: Using flow cytometry, ELISA and immunohistochemistry, expression of natural killer cell receptor ligands was assessed in chemotherapy-sensitive/-resistant Ewing sarcoma cell lines, plasma and tumours. Natural killer cell cytotoxicity was evaluated in Chromium release assays. Using ATM/ATR inhibitor caffeine, the contribution of the DNA damage response pathway to histone deacetylase inhibitor-induced ligand expression was assessed.

Results: Despite comparable expression of natural killer cell receptor ligands, chemotherapy-resistant Ewing sarcoma exhibited reduced susceptibility to resting natural killer cells. Interleukin-15-activation of natural killer cells overcame this reduced sensitivity. Histone deacetylase inhibitor-pretreatment induced NKG2D-ligand expression in an ATM/ATR-dependent manner and sensitized for NKG2D-dependent cytotoxicity (2/4 cell lines). NKG2D-ligands were expressed in vivo, regardless of chemotherapy-response and disease stage. Soluble NKG2D-ligand plasma concentrations did not differ between patients and controls.

Conclusion: Our data provide a rationale for combination immunotherapy involving immune effector and target cell manipulation in first-/second-line treatment regimens for Ewing sarcoma.
KW  - Ewing sarcoma
KW  - natural killer cells
KW  - histone deacetylase inhibitor
KW  - combination immunotherapy
KW  - chemotherapy-resistance
KW  - tumour immunology
Y1  - 2012
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/24068
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-240683
SN  - 2045-3329
VL  - 2
IS  - 8
PB  - BioMed Central
CY  - London
ER  -