Identification of a meiosis-specific protein, MEIOB, as a novel cancer/testis antigen and its augmented expression in demethylated cancer cells.
Cancer/testis (CT) antigens, which are expressed in various cancer cells but not in normal cells except germline cells of the testis, have been used as targets for cancer vaccine therapy. 5-Aza-2'-deoxycytidine (DAC), a potent inhibitor of genomic and promoter-specific DNA methylation, inhibits DNA methyltransferase activity and is reported to induce the expression of certain CT antigens by the demethylation of promoter CpG islands of the treated cells. Here, using DAC-treated cancer cells, we searched for novel attractive target molecules that would be useful for cancer immunotherapy and found a meiosis-specific protein, meiosis specific with OB domains (MEIOB), to be a novel CT antigen. Indeed, the MEIOB gene is expressed only in the testis and not in other normal tissues. The mRNA expression of MEIOB was greatly enhanced in several lung cancer cell lines after the treatment with DAC. Furthermore, we identified a variety of helper epitopes of the MEIOB antigen, which were recognized by MEIOB antigen-specific T cells in a HLA-restriction manner. Finally, we demonstrated that IFN-γ production of MEIOB peptide-specific helper T cells in response to HLA-matched cancer cells was greatly augmented by treatment with DAC and IFN-γ. Taken together, these findings show DAC to be a promising tool for finding novel CT antigens and for developing a future novel combination cancer vaccine chemotherapy.
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
Yasuo
Y
Shiohama
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
Junya
J
Ohtake
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
Takayuki
T
Ohkuri
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
Daisuke
D
Noguchi
BioImmulance Co., Ltd., Shin-ei-363-32, Kiyota-ku, Sapporo 004-0839, Japan.
Yuji
Y
Togashi
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
Hidemitsu
H
Kitamura
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan; Division of ROYCE' Health Bioscience, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan. Electronic address: tak24@igm.hokudai.ac.jp.
Takashi
T
Nishimura
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D018604:Epitope Mapping; D015972:Gene Expression Regulation, Neoplastic; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology* / Q000628:therapy*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008540:Meiosis / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D013737:Testis / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D006680:HLA Antigens; C587161:MEIOB protein, human; D010446:Peptide Fragments; D003570:Cytidine Triphosphate; C038673:5-aza-2'-deoxycytidine-5'-triphosphate; D007371:Interferon-gamma; D001374:Azacitidine
5-Aza-2′-deoxycytidine; Cancer immunotherapy; Cancer testis antigen; Demethylation; Helper epitope; Meiosis specific with OB domains