Dannull J, Diener P A, Prikler L, Fürstenberger G, Cerny T, Schmid U, Ackermann D K, Groettrup M
Department of Laboratory Research, Cantonal Hospital St Gall, Gallen, Switzerland.
Cancer Res. 2000 Oct 1;60(19):5522-8.
Immunotherapy of prostate cancer (CaP) may be a promising novel treatment option for the management of advanced CaP. However, the lack of suitable tumor antigens remains a major obstacle for the rational design of vaccines. To characterize potential CaP antigens, we determined the mRNA expression of the prostate-specific genes C1, C2, C5, PAGE-1, and prostate stem cell antigen (PSCA) in hormone-refractory CaP, benign prostatic hyperplasia, CaP cell lines, and CaP specimens. Among these gene products, only expression of PSCA appears to be retained in the majority of advanced CaP samples, as shown by reverse transcription-PCR analyses. Peptide fragments of PSCA presented in the context of major histocompatibility molecules could serve as recognition targets for CD8 T cells, provided these lymphocytes were not clonally deleted or peripherally tolerized. Our goal was to determine whether the human T-cell repertoire could recognize PSCA-derived peptide epitopes in the context of a common class I allele, HLA-A0201. Of nine peptides that, according to HLA-A0201 binding motifs, were candidate ligands of A0201 class I molecules, three peptides were able to stabilize HLA-A0201 molecules on the cell surface. One of the latter peptides, encompassing amino acid residues 14-22, was capable of generating a PSCA-specific T-cell response in a human lymphocyte culture from a patient with metastatic CaP. PSCA-specific CTLs recognized peptide-pulsed targets as well as three prostate carcinoma lines in cytotoxicity assays, indicating that this peptide could be endogenously processed. In conclusion, our findings establish PSCA as a potential target for antigen-specific, T cell-based immunotherapy of prostate carcinoma.
前列腺癌（CaP）的免疫疗法可能是晚期CaP治疗的一种有前景的新选择。然而，缺乏合适的肿瘤抗原仍然是合理设计疫苗的主要障碍。为了鉴定潜在的CaP抗原，我们测定了激素难治性CaP、良性前列腺增生、CaP细胞系和CaP标本中前列腺特异性基因C1、C2、C5、PAGE-1和前列腺干细胞抗原（PSCA）的mRNA表达。在这些基因产物中，如逆转录-PCR分析所示，只有PSCA的表达在大多数晚期CaP样本中似乎得以保留。如果这些淋巴细胞没有被克隆性删除或在外周形成耐受，主要组织相容性分子提呈的PSCA肽片段可作为CD8 T细胞的识别靶点。我们的目标是确定人类T细胞库是否能在常见的I类等位基因HLA-A0201背景下识别PSCA衍生的肽表位。根据HLA-A0201结合基序，九种肽是A0201 I类分子的候选配体，其中三种肽能够稳定细胞表面的HLA-A0201分子。后一种肽中的一种，包含氨基酸残基14 - 22，能够在一名转移性CaP患者的人淋巴细胞培养物中产生PSCA特异性T细胞应答。在细胞毒性试验中，PSCA特异性CTL识别肽脉冲靶细胞以及三种前列腺癌细胞系，表明该肽可被内源性加工。总之，我们的研究结果确定PSCA为前列腺癌抗原特异性、基于T细胞的免疫疗法的潜在靶点。
