title: Hypomethylating drugs convert HA-1-negative solid tumors into targets for stem cell-based immunotherapy.
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.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, The Netherlands. l.w.h.hambach@lumc.nl
authors.forename: Lothar
authors.initials: L
authors.lastname: Hambach
authors.forename: Kam-Wing
authors.initials: KW
authors.lastname: Ling
authors.forename: Jos
authors.initials: J
authors.lastname: Pool
authors.forename: Zohara
authors.initials: Z
authors.lastname: Aghai
authors.forename: Els
authors.initials: E
authors.lastname: Blokland
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Tanke
authors.forename: Jan A
authors.initials: JA
authors.lastname: Bruijn
authors.forename: Hans
authors.initials: H
authors.lastname: Halfwerk
authors.forename: Hester
authors.initials: H
authors.lastname: van Boven
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wieles
authors.forename: Els
authors.initials: E
authors.lastname: Goulmy
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019175:DNA Methylation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods*; D015778:Minor Histocompatibility Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009842:Oligopeptides / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: D000951:Antigens, Neoplasm; D004273:DNA, Neoplasm; C110615:HA-1 antigen; D006657:Histones; D006877:Hydroxamic Acids; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C012589:trichostatin A; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine