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2015 ; 10
(10
): e0139221
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gab.com Text
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Treatment with 5-Aza-2 -Deoxycytidine Induces Expression of NY-ESO-1 and
Facilitates Cytotoxic T Lymphocyte-Mediated Tumor Cell Killing
#MMPMID26447882
Klar AS
; Gopinadh J
; Kleber S
; Wadle A
; Renner C
PLoS One
2015[]; 10
(10
): e0139221
PMID26447882
show ga
BACKGROUND: NY-ESO-1 belongs to the cancer/testis antigen (CTA) family and
represents an attractive target for cancer immunotherapy. Its expression is
induced in a variety of solid tumors via DNA demethylation of the promoter of CpG
islands. However, NY-ESO-1 expression is usually very low or absent in some
tumors such as breast cancer or multiple myeloma. Therefore, we established an
optimized in vitro treatment protocol for up-regulation of NY-ESO-1 expression by
tumor cells using the hypomethylating agent 5-aza-2'-deoxycytidine (DAC).
METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated de novo induction of NY-ESO-1 in
MCF7 breast cancer cells and significantly increased expression in U266 multiple
myeloma cells. This effect was time- and dose-dependent with the highest
expression of NY-ESO-1 mRNA achieved by the incubation of 10 ?M DAC for 72 hours.
NY-ESO-1 activation was also confirmed at the protein level as shown by Western
blot, flow cytometry, and immunofluorescence staining. The detection and
quantification of single NY-ESO-1 peptides presented at the tumor cell surface in
the context of HLA-A*0201 molecules revealed an increase of 100% and 50% for MCF7
and U266 cells, respectively. Moreover, the enhanced expression of NY-ESO-1
derived peptides at the cell surface was accompanied by an increased specific
lysis of MCF7 and U266 cells by HLA-A*0201/NY-ESO-1(157-165) peptide specific
chimeric antigen receptor (CAR) CD8+ T cells. In addition, the killing activity
of CAR T cells correlated with the secretion of higher IFN-gamma levels.
CONCLUSIONS/SIGNIFICANCE: These results indicate that NY-ESO-1 directed
immunotherapy with specific CAR T cells might benefit from concomitant DAC
treatment.
|Antigens, Neoplasm/genetics/*metabolism
[MESH]
|Azacitidine/*analogs & derivatives/pharmacology/therapeutic use
[MESH]