Correale P, Walmsley K, Zaremba S, Zhu M, Schlom J, Tsang K Y
Laboratory of Tumor Immunology and Biology, Division of Basic Science, National Cancer Institute, Bethesda, MD 20892, USA.
J Immunol. 1998 Sep 15;161(6):3186-94.
Prostate-specific Ag (PSA), which is expressed in a majority of prostate cancers, is a potential target for specific immunotherapy. Previous studies have shown that two 10-mer PSA peptides (designated PSA-1 and PSA-3) selected to conform to human HLA class I-A2 motifs can elicit CTL responses in vitro. A longer PSA peptide (30-mer) designated PSA-OP (oligoepitope peptide), which contains both the PSA-1 and PSA-3 HLA-A2 epitopes and an additional potential CTL epitope (designated PSA-9) for the HLA-class I-A3 allele, was investigated for the ability to induce cytotoxic T cell activity. T cell lines from different HLA-A2 and HLA-A3 donors were established by in vitro stimulation with PSA-OP; the CTL lines lysed PSA-OP as well as PSA-1- or PSA-3-pulsed C1R-A2 cells, and PSA-OP and PSA-9-pulsed C1R-A3 cells, respectively. The CTL lines derived from the PSA-OP peptide also lysed PSA-positive prostate cancer cells. PSA-OP-derived T cell lines also lysed recombinant vaccinia-PSA-infected targets but not targets infected with wild-type vaccinia. PSA-OP did not bind HLA-A2 and HLA-A3 molecules. The decrease in cytotoxicity in the presence of protease inhibitors suggests that the PSA-OP is cleaved into shorter peptides, which in turn can interact with HLA-class I molecules and, as a consequence, induce CTL-mediated lysis. We have also demonstrated that it is possible to induce CTL responses in HLA-A2.1/Kb transgenic mice by immunization with PSA-OP with adjuvant. These studies thus provide evidence that oligopeptides such as PSA-OP may be useful candidates for peptide-based cancer vaccines.
前列腺特异性抗原（PSA）在大多数前列腺癌中表达，是特异性免疫治疗的潜在靶点。先前的研究表明，选择符合人类HLA I-A2基序的两种10聚体PSA肽（命名为PSA-1和PSA-3）可在体外引发CTL反应。研究了一种更长的PSA肽（30聚体），命名为PSA-OP（寡表位肽），它包含PSA-1和PSA-3 HLA-A2表位以及一个针对HLA I-A3等位基因的额外潜在CTL表位（命名为PSA-9）诱导细胞毒性T细胞活性的能力。通过用PSA-OP体外刺激建立了来自不同HLA-A2和HLA-A3供体的T细胞系；这些CTL系分别裂解PSA-OP以及PSA-1或PSA-3脉冲处理的C1R-A2细胞，以及PSA-OP和PSA-9脉冲处理的C1R-A3细胞。源自PSA-OP肽的CTL系也裂解PSA阳性前列腺癌细胞。源自PSA-OP的T细胞系也裂解重组痘苗-PSA感染的靶细胞，但不裂解野生型痘苗感染的靶细胞。PSA-OP不结合HLA-A2和HLA-A3分子。蛋白酶抑制剂存在下细胞毒性的降低表明PSA-OP被切割成更短的肽，这些肽进而可与HLA I类分子相互作用，从而诱导CTL介导的裂解。我们还证明，用PSA-OP与佐剂免疫可在HLA-A2.1/Kb转基因小鼠中诱导CTL反应。因此，这些研究提供了证据，表明诸如PSA-OP之类的寡肽可能是基于肽的癌症疫苗的有用候选物。
