Aberrant expression and potency as a cancer immunotherapy target of alpha-methylacyl-coenzyme A racemase in prostate cancer

Ichiya Honma,Yasuaki Tamura,Toshihiko Torigoe,Naoya Masumori,Noriyuki Sato,Eiji Sato,Taiji Tsukamoto,Hiroshi Kitamura,Yoshihiko Hirohashi

doi:10.1186/1479-5876-7-103

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

Introduction

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

Methods

Results

Discussion

Conclusion