| RRC ID |
19311
|
| 著者 |
Hambach L, Ling KW, Pool J, Aghai Z, Blokland E, Tanke HJ, Bruijn JA, Halfwerk H, van Boven H, Wieles B, Goulmy E.
|
| タイトル |
Hypomethylating drugs convert HA-1-negative solid tumors into targets for stem cell-based immunotherapy.
|
| ジャーナル |
Blood
|
| Abstract |
Clinical responses of solid tumors after allogeneic human leukocyte antigen-matched stem cell transplantation (SCT) often coincide with severe graft-versus-host disease (GVHD). Targeting minor histocompatibility antigens (mHags) with hematopoiesis- and cancer-restricted expression, for example, HA-1, may allow boosting the antitumor effect of allogeneic SCT without risking severe GVHD. The mHag HA-1 is aberrantly expressed in cancers of most entities. However, an estimated 30% to 40% of solid tumors do not express HA-1 (ie, are HA-1(neg)) and cannot be targeted by HA-1-specific immunotherapy. Here, we investigated the transcriptional regulation of HA-1 gene expression in cancer. We found that DNA hypermethylation in the HA-1 promoter region is closely associated with the absence of HA-1 gene expression in solid tumor cell lines. Moreover, we detected HA-1 promoter hypermethylation in primary cancers. The hypomethylating agent 5-aza-2'-deoxycytidine induced HA-1 expression only in HA-1(neg) tumor cells and sensitized them for recognition by HA-1-specific cytotoxic T lymphocytes. Contrarily, the histone deacetylation inhibitor trichostatin A induced HA-1 expression both in some HA-1(neg) tumor cell lines and in normal nonhematopoietic cells. Our data suggest that promoter hypermethylation contributes to the HA-1 gene regulation in tumors. Hypomethylating drugs might extend the safe applicability of HA-1 as an immunotherapeutic target on solid tumors after allogeneic SCT.
|
| 巻・号 |
113(12)
|
| ページ |
2715-22
|
| 公開日 |
2009-3-19
|
| DOI |
10.1182/blood-2008-05-158956
|
| PII |
S0006-4971(20)37537-6
|
| PMID |
19096014
|
| MeSH |
Acetylation / drug effects
Antigens, Neoplasm / biosynthesis*
Antigens, Neoplasm / genetics
Antigens, Neoplasm / immunology
Azacitidine / analogs & derivatives*
Azacitidine / pharmacology
Azacitidine / therapeutic use
Cell Line, Tumor / drug effects
Cell Line, Tumor / metabolism
CpG Islands
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
DNA Methylation / drug effects*
DNA, Neoplasm / drug effects*
Decitabine
Gene Expression Regulation, Neoplastic / drug effects*
Gene Silencing / drug effects*
Histones / metabolism
Humans
Hydroxamic Acids / pharmacology
Immunotherapy / methods*
Minor Histocompatibility Antigens / biosynthesis*
Minor Histocompatibility Antigens / genetics
Minor Histocompatibility Antigens / immunology
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / metabolism
Neoplasms / genetics*
Neoplasms / immunology
Neoplasms / pathology
Oligopeptides / biosynthesis*
Oligopeptides / genetics
Oligopeptides / immunology
Promoter Regions, Genetic / drug effects
Promoter Regions, Genetic / genetics
Protein Processing, Post-Translational / drug effects
RNA, Messenger / biosynthesis
RNA, Neoplasm / biosynthesis
T-Lymphocytes, Cytotoxic / immunology
Transcription, Genetic
|
| IF |
17.794
|
| 引用数 |
31
|
|
WOS 分野
|
HEMATOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
OCUB-F(RCB0882) |
