Document Detail


Chimeric NKG2D CAR-expressing T cell-mediated attack of human ovarian cancer is enhanced by histone deacetylase inhibition.
MedLine Citation:
PMID:  23297870     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
NKG2D ligands (NKG2DLs) are widely expressed on ovarian cancers to various degrees, making them attractive targets for immunotherapy. Here, we applied a chimeric antigen receptor (CAR) approach for the targeting of NKG2DLs expressed on human ovarian cancer cells and evaluated the impact of pharmacological upregulation of NKG2DLs on immune recognition. Various NKG2DLs, including MICA/B and ULBP-1, -2, -3, and -4, were expressed at various levels on the surface of all established ovarian cancer cell lines and primary ovarian cancer samples tested. To redirect human T cells against NKG2DLs, an NKG2DL-specific CAR was generated by fusing the extracellular domain of the NKG2D receptor to the 4-1BB costimulatory and CD3-ζ chain signaling domains. In vitro expansion of chimeric NKG2D CAR T cells was delayed compared with untransduced T cells and control CAR T cells; the likely result of fratricide among activated T cells expressing NKG2DLs. However, NKG2D CAR T cells did expand and were selectively enriched during prolonged culture. In coculture, CD4(+) and CD8(+) NKG2D CAR T cells specifically recognized and killed NKG2DL-expressing ovarian cancer cell lines but not NKG2DL-negative cells. Notably, pretreatment of ovarian cancer cells expressing moderate to low levels of NKG2DLs with the histone deacetylase inhibitor sodium valproate (VPA) upregulated NKG2DL cell surface expression and consequently enhanced their immune recognition by chimeric NKG2D CAR T cells. Our results demonstrate that VPA-induced upregulation of NKG2DL expression enhances the immune recognition of ovarian cancer cells by engineered NKG2D CAR T cells, and rationalizes the use of VPA in combination with NKG2DL-targeted immunotherapy in ovarian cancer.
Authors:
De-Gang Song; Qunrui Ye; Stephen Santoro; Chongyun Fang; Andrew Best; Daniel J Powell
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-03-01
Journal Detail:
Title:  Human gene therapy     Volume:  24     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-21     Completed Date:  2013-09-06     Revised Date:  2014-07-18    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  295-305     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Cell Line
Female
Gene Expression
Gene Expression Regulation, Neoplastic / drug effects
Gene Order
Genetic Vectors / genetics
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylases / metabolism*
Humans
Immunophenotyping
Lentivirus / genetics
Ligands
Lymphocyte Activation
NK Cell Lectin-Like Receptor Subfamily K / genetics*,  metabolism
Ovarian Neoplasms / genetics*,  immunology*,  metabolism
Phenotype
Receptors, Antigen, T-Cell / genetics*,  metabolism
T-Lymphocytes / immunology*,  metabolism*
Valproic Acid / pharmacology
Grant Support
ID/Acronym/Agency:
P30 CA016520/CA/NCI NIH HHS; P50 CA083638/CA/NCI NIH HHS; R01 CA168900/CA/NCI NIH HHS; R01-CA168900/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Histone Deacetylase Inhibitors; 0/Ligands; 0/NK Cell Lectin-Like Receptor Subfamily K; 0/Receptors, Antigen, T-Cell; 614OI1Z5WI/Valproic Acid; EC 3.5.1.98/Histone Deacetylases
Comments/Corrections

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