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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Antigens, Neoplasm / biosynthesis*
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology
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Azacitidine / analogs & derivatives*
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Azacitidine / pharmacology
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Azacitidine / therapeutic use
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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CpG Islands
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
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DNA Methylation / drug effects*
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DNA, Neoplasm / drug effects*
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Decitabine
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Gene Expression Regulation, Neoplastic / drug effects*
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Gene Silencing / drug effects*
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Histones / metabolism
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Humans
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Hydroxamic Acids / pharmacology
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Immunotherapy / methods*
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Minor Histocompatibility Antigens / biosynthesis*
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Minor Histocompatibility Antigens / genetics
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Minor Histocompatibility Antigens / immunology
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / metabolism
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Neoplasms / genetics*
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Neoplasms / immunology
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Neoplasms / pathology
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Oligopeptides / biosynthesis*
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Oligopeptides / genetics
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Oligopeptides / immunology
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / genetics
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Protein Processing, Post-Translational / drug effects
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RNA, Messenger / biosynthesis
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RNA, Neoplasm / biosynthesis
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T-Lymphocytes, Cytotoxic / immunology
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Transcription, Genetic
Substances
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Antigens, Neoplasm
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DNA, Neoplasm
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HA-1 antigen
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Histones
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Hydroxamic Acids
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Minor Histocompatibility Antigens
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Neoplasm Proteins
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Oligopeptides
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RNA, Messenger
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RNA, Neoplasm
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trichostatin A
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Decitabine
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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Azacitidine