Antitumor cytotoxic T-cell response induced by a survivin peptide mimic.
Antitumor cytotoxic T-cell response induced by a survivin peptide mimic.
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DOI：
10.1007/s00262-010-0845-x
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发表时间：
2010-08
期刊：
影响因子：
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通讯作者：
Fenstermaker RA
中科院分区：
文献类型：
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作者：
Ciesielski MJ;Ahluwalia MS;Munich SA;Orton M;Barone T;Chanan-Khan A;Fenstermaker RA
Survivin是一种肿瘤相关抗原，具有作为癌症疫苗靶点的巨大潜力。我们已经确定了一个生存素肽模拟物含有人类MHC I类表位和一个潜在的II类配体，诱导一个有效的抗肿瘤反应，在C57 BL/6小鼠与GL 261脑胶质瘤。该肽能够在C57 BL/6小鼠中引发CD 8 + CTL和T辅助细胞应答。由肽SVN 53 -67代表的人存活素分子的相应区域与鼠蛋白100%同源，我们评估了SVN 53 -67中假定的人MHC I锚位置的几个氨基酸替换，67鉴定潜在的肽模拟物，其可以提供针对人胶质瘤和原发性中枢神经系统的增强的抗肿瘤免疫应答。淋巴瘤（PCNSL）细胞。我们使用来自这些恶性肿瘤患者PBMC的负载肽的树突状细胞评估了预测与人类HLA-A*0201抗原结合的存活素肽。一个改变（M57）导致以显著更高的亲和力与HLA-A*0201结合。我们比较了负载有SVN 53 -67肽和SVN 53 -67/M57的自体树突状细胞在CTL测定中针对同种异体和自体的表达存活素的人恶性胶质瘤和PCNSL细胞的能力。SVN 53 -67和SVN 53 -67/M57均产生CTL介导的恶性靶细胞杀伤;然而，SVN 53 -67/M57比SVN 53 -67显著更有效。因此，SVN 53 -67/M57可以作为肽模拟物在肿瘤患者中诱导增强的抗肿瘤CTL应答。SVN 53 -67/M57作为癌症疫苗的用途可能具有癌症疫苗治疗的应用。
Survivin is a tumor-associated antigen with significant potential as a cancer vaccine target. We have identified a survivin peptide mimic containing human MHC class I epitopes and a potential class II ligand that induces a potent antitumor response in C57BL/6 mice with GL261 cerebral gliomas. This peptide is able to elicit both CD8+ CTL and T helper cell responses in C57BL/6 mice. The corresponding region of the human survivin molecule represented by peptide SVN53-67 is 100% homologous to the murine protein, but SVN53-67 is weakly immunogenic in man. We evaluated several amino acid substitutions in putative human MHC I anchor positions in SVN53-67 to identify potential peptide mimics that could provide an enhanced antitumor immune response against human glioma and primary central nervous system lymphoma (PCNSL) cells in culture. We evaluated survivin peptides with predicted binding to human HLA-A*0201 antigen using peptide-loaded dendritic cells from PBMC of patients with these malignancies. One alteration (M57) led to binding to HLA-A*0201 with significantly higher affinity. We compared the ability of autologous dendritic cells loaded with SVN53-67 peptide and SVN53-67/M57 in CTL assays against allomatched and autologous, survivin-expressing, human malignant glioma and PCNSL cells. Both SVN53-67 and SVN53-67/M57 produced CTL-mediated killing of malignant target cells; however, SVN53-67/M57 was significantly more effective than SVN53-67. Thus, SVN53-67/M57 may act as a peptide mimic to induce an enhanced antitumor CTL response in tumor patients. The use of SVN53-67/M57 as a cancer vaccine might have application for cancer vaccine therapy.