Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
J Transl Med. 2009 Dec 9;7:103. doi: 10.1186/1479-5876-7-103.
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.
α-甲基酰基辅酶 A 消旋酶（AMACR）在支链脂肪酸和脂肪酸衍生物的β-氧化中起着重要作用。AMACR 的高表达水平已在各种癌症中描述，包括前列腺癌、结直肠癌和肾癌。由于其具有癌症特异性和频繁表达，因此 AMACR 可能成为基于细胞毒性 T 淋巴细胞（CTL）的癌症免疫治疗的有吸引力的靶标。在本研究中，我们从前列腺癌患者的外周血单核细胞（PBMC）中检查了 AMACR 特异性 CTL 的诱导，并确定了 HLA-A24 限制性 CTL 表位。RT-PCR 和免疫组织化学分析显示，与良性或正常前列腺组织相比，AMACR 在前列腺癌细胞系和组织中强烈表达。从该蛋白的氨基酸序列合成了四个携带 HLA-A24 结合基序的 AMACR 衍生肽，并对其与 HLA-A24 的结合亲和力进行了分析。通过用肽刺激患者的 PBMC，在 11 名患者中的 6 名中成功诱导了特异性 CTL。肽特异性 CTL 在 HLA-A24 背景下对表达 AMACR 的前列腺癌细胞表现出显著的细胞毒性活性。我们的研究表明，AMACR 可能成为前列腺癌免疫治疗的靶标，并且 AMACR 衍生肽可能是 HLA-A24 阳性 AMACR 表达癌症患者的良好肽疫苗候选物。
