Histone deacetylase inhibitors enhance expression of NKG2D ligands in Ewing sarcoma and sensitize for natural killer cell-mediated cytolysis

Clinical Sarcoma Research

Arjan C Lankester²  Pancras CW Hogendoorn³  R Maarten Egeler²  Emilie P Buddingh'²  Stephan Kloess¹  Susy J Santos²  Hanneke I Vos²  Marco W Schilham²  Dagmar Berghuis² 

[1] Laboratory for Stem Cell Transplantation and Immunotherapy, Hospital of Johann Wolfgang Goethe-University, Frankfurt am Main, Germany;Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

关键词: tumour immunology;    chemotherapy-resistance;    combination immunotherapy;    histone deacetylase inhibitor;    natural killer cells;    Ewing sarcoma;   

Others  :  862976
DOI  :  10.1186/2045-3329-2-8

 received in 2012-01-03, accepted in 2012-02-08,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Berghuis et al; licensee BioMed Central Ltd.

【 图 表 】

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