Abstract
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.
Highlights
Cytotoxic T lymphocytes (CTLs) play a major role in the anti-cancer immune response [1]
Our study demonstrates for the first time HLA-A24-restricted Alpha-methylacyl coenzyme A racemase (AMACR)-derived CTL epitopes that might be suitable for peptide vaccines for AMACR-expressing cancer patients
We detected the overt expression of β-actin mRNA and AMACR mRNA in prostate cancer line LNCaP, but only very weak expression of AMACR mRNA was observed in normal adult liver and pancreas (Figure 1A)
Summary
Cytotoxic T lymphocytes (CTLs) play a major role in the anti-cancer immune response [1]. CTL epitope peptides derived from tumor-specific antigens like the MAGE gene family have been employed for pioneering studies of immunotherapy in cases of advanced melanoma patients [4,5]. Alpha-methylacyl coenzyme A racemase (AMACR) was identified as one of the genes that were highly expressed in prostate cancer tissues through gene expression profiling using a DNA microarray and RT-PCR [6,7,8]. Immunohistochemical staining for AMACR is currently used in the clinical setting to support the histological diagnosis of prostate cancer Because it has characteristics of cancer-specific expression and frequent expression in various cancers, AMACR is an attractive target for cancer immunotherapy. Our study demonstrates for the first time HLA-A24-restricted AMACR-derived CTL epitopes that might be suitable for peptide vaccines for AMACR-expressing cancer patients
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