RRC ID 19311
Author Hambach L, Ling KW, Pool J, Aghai Z, Blokland E, Tanke HJ, Bruijn JA, Halfwerk H, van Boven H, Wieles B, Goulmy E.
Title Hypomethylating drugs convert HA-1-negative solid tumors into targets for stem cell-based immunotherapy.
Journal 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.
Volume 113(12)
Pages 2715-22
Published 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
Times Cited 31
Human and Animal Cells OCUB-F(RCB0882)