Aberrant expression and potency as a cancer immunotherapy target of alpha-methylacyl-coenzyme A racemase in prostate cancer.
Alpha-methylacyl-CoA racemase (AMACR) is an enzyme playing an important role in the beta-oxidation of branched-chain fatty acids and fatty acid derivatives. High expression levels of AMACR have been described in various cancers, including prostate cancer, colorectal cancer and kidney cancer. Because of its cancer-specific and frequent expression, AMACR could be an attractive target for cytotoxic T-lymphocyte (CTL)-based immunotherapy for cancer. In the present study, we examined the induction of AMACR-specific CTLs from prostate cancer patients' peripheral blood mononuclear cells (PBMCs) and determined HLA-A24-restricted CTL epitopes.RT-PCR and immunohistochemical analysis revealed that AMACR was strongly expressed in prostate cancer cell lines and tissues as compared with benign or normal prostate tissues. Four AMACR-derived peptides carrying the HLA-A24-binding motif were synthesized from the amino acid sequence of this protein and analyzed to determine their binding affinities to HLA-A24. By stimulating patient's PBMCs with the peptides, specific CTLs were successfully induced in 6 of 11 patients. The peptide-specific CTLs exerted significant cytotoxic activity against AMACR-expressing prostate cancer cells in the context of HLA-A24. Our study demonstrates that AMACR could become a target antigen for prostate cancer immunotherapy, and that the AMACR-derived peptides might be good peptide vaccine candidates for HLA-A24-positive AMACR-expressing cancer patients.
Honma
Ichiya
I
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan. ichiya@sapmed.ac.jp
Torigoe
Toshihiko
T
Hirohashi
Yoshihiko
Y
Kitamura
Hiroshi
H
Sato
Eiji
E
Masumori
Naoya
N
Tamura
Yasuaki
Y
Tsukamoto
Taiji
T
Sato
Noriyuki
N
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D000939:Epitopes; D015234:HLA-A Antigens / Q000235:genetics / Q000378:metabolism; D059871:HLA-A24 Antigen; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D011485:Protein Binding; D019998:Racemases and Epimerases / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution
D000939:Epitopes; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D010455:Peptides; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase