Identification of human tumor antigens and immunotherapy

人类肿瘤抗原的鉴定和免疫治疗

• 批准号: 11694301
• 负责人: SATO Noriyuki
• 金额: $ 8.28万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11694301/
• 关键词: tumor vaccine; CTL; immunotherapy; HLA-A24; antigenic peptide; hsc73; molecular chaperone; ER translocation; ヒト癌抗原; 抗原ペプチド; hsc 70; 癌抗原遺伝子; HLA-A31; HLA-DR8; 癌抗原; キラーT細胞; HLA; αエノラーゼ; リカバリン; CAR; SYT-SSX融合蛋白

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.

我们的研究表明，1）凋亡抑制剂（IAP）蛋白优先在肿瘤细胞中表达，但在正常组织中不表达。这种 IAP，特别是生存素和生存素衍生的 HLA-A24 限制性肽可能对癌症患者具有免疫原性。 2) 在50%以上的癌细胞和癌组织中也检测到了通常在视网膜中表达的Recoverin蛋白。 Recoverin 衍生的 HLA-A24 限制性肽还可以在各种组织来源的癌症患者中特异性诱导 CTL。 3) SYT-SSX染色体易位(X;18)融合蛋白在约95%的滑膜肉瘤中特异表达。这种蛋白衍生的 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 的前体在该肿瘤肺转移的患者中更频繁地检测到。这些数据表明上述肽可能在人类癌症免疫治疗中有用。我们还评估了分子伴侣hsc73在抗原肽转运至ER中的作用。数据表明，对 hsc73 表现出高亲和力但不低亲和力的 N 末端延伸肽可以进入 ER。这一观察结果对于确定肿瘤疫苗很重要，因为 hsc73 结合肽可能优先与 MHC I 类分子相关。

项目成果

Maeda, A., Ohguro, H., Nabeta, Y., Kuroki, Y., Sato, N.et al.: "Identification of human antitumor cytotoxic T lymphocytes epitopes of recoverin, cancer associated retinopathy antige, to achieve a clinical better prognosis in a paraneoplastic syndrome"Eur.

Maeda, A.、Ohguro, H.、Nabeta, Y.、Kuroki, Y.、Sato, N.等人：“鉴定人类抗肿瘤细胞毒性 T 淋巴细胞恢复蛋白、癌症相关视网膜病变抗原的表位，以实现更好的临床

Maeda, A., Ohguro, H., Nabeta, Y., Hirohashi, Y., Sahara, H., Maeda, T., Wada, Y., Sato, T., Chuns, Y., Nishimura, Y., Kuroki, Y., and Sato, N.: "Identification of human antitumor cytotoxic T lymphocytes epitopes of recoverin, cancer associated retinopath

前田，A.，大黑，H.，Nabeta，Y.，广桥，Y.，撒哈拉，H.，前田，T.，和田，Y.，佐藤，T.，春斯，Y.，西村，Y.，

Sahara, H., Nabeta, Y., Torigoe, T., Hirohashi, Y., Ichimiya, S., Wada, Y., Takehashi, N., Jimbow, K., Yajima, T., Watanabe, N., Kikuchi, K., and Sato, N.: "A gene encoding human gastric signete ring cell carcinoma antigen recognized by HLA-A31-restricted

撒哈拉，H.，Nabeta，Y.，Torigoe，T.，广桥，Y.，Ichimiya，S.，和田，Y.，竹桥，N.，Jimbow，K.，矢岛，T.，渡边，N.，

Sato, Y., Nabeta, Y., Tsukahara, T., Hirohashi, Y., Rone. S., Maeda, A., Sajara, H., Ikeda, H., Torigoe, T., Ichimiya, S., Wada, T., Yamashita, T., Hiraga, R, Kawai, A., Ishii, T., Araki, N., Kmyoui, A., Matsumoto, S., Umeda, T., Ishii, S., Kawaguchi, S.

佐藤，Y.，Nabeta，Y.，冢原，T.，广桥，Y.，罗恩。

Kikuchi,K.,and Sato,N.: "Gann Monogr.J.Cancer Res."Cell-mediated Immunity to autologous cancer.Rationale of immunotherapy of human cancer with CTL.. 12 (1999)

Kikuchi，K.，和 Sato，N.：“Gann Monogr.J.Cancer Res.”细胞介导的自体癌症免疫。用 CTL 进行人类癌症免疫治疗的基本原理.. 12 (1999)