Identification of human tumor antigens and immunotherapy

我们的研究表明：（1）凋亡抑制因子（IAP）蛋白在肿瘤细胞中优先表达，而在正常组织中不表达;这样的IAP，特别是生存素和livin衍生的HLA-A24限制性肽可能对癌症患者具有免疫原性。2)通常在视网膜中表达的恢复蛋白也在超过50%的癌细胞和癌组织中检测到。回收素衍生的HLA-A24限制性肽也可在各种组织来源的癌症患者中特异性地诱导CTL。3)SYT-SSX染色体易位（X;18）融合蛋白在约95%的滑膜肉瘤中特异性表达。该蛋白衍生的HLA-A24限制性肽可以诱导抗原特异性CTL，四聚体研究表明，这些CTL的前体在该肿瘤的肺转移患者中更频繁地被检测到。这些结果表明，上述肽可能是有用的人类癌症免疫治疗。我们还评估了分子伴侣，hsc 73在抗原肽转运到ER的作用。这些数据表明，对hsc 73表现出高而非低亲和力的N-末端延伸肽可以进入ER。这一观察结果在确定肿瘤疫苗中很重要，因为hsc 73结合肽可能优先与MHC I类分子相关。

Our studies indicated that 1) inhibitors of apoptosis (IAP) protein were expressed preferentially in neoplastic cells but not in normal tissues. Such IAP, particulary, survivin-and livin-derived HLA-A24-restricted peptides could be immunogenic to cancer patients. 2) Recoverin protein that normally expresses in retina was also detected in more than 50 % of cancer cells and cancer tissues. Recoverin-derived HLA-A24-restricted peptide could also specifically induce CTL in the cancer patients of various tissue origins. 3) SYT-SSX chromosomal translocation (X;18) fusion protein was expressed specifically in approximately 95 % of synovial sarcomas. This protein-derived HLA-A24-restricted peptide could induce antigen-specific CTL, and tetramer study suggested that the precursor of these CTL was detected more frequently in patients with lung metastasis of this tumor. These data implied that above peptides may be useful in human cancer immunotherapy.We also assessed the role of molecular chaperone, hsc73, in the transport of antigenic peptide into the ER. The data indicated that N-terminus-extended peptides that showed high, but not low, affinity to hsc73 could enter into the ER. This observation is important in determining tumor vaccines, because hsc73-binding peptides may be preferentially associated with MHC class I molecules.