Mouse homologue of a novel human oncofetal antigen, glypican-3, evokes T-cell-mediated tumor rejection without autoimmune reactions in mice
Mouse homologue of a novel human oncofetal antigen, glypican-3, evokes T-cell-mediated tumor rejection without autoimmune reactions in mice
复制标题
DOI：
10.1158/1078-0432.ccr-04-1177
复制
发表时间：
2004-12-15
影响因子：
11.5
通讯作者：
Nishimura, Y
中科院分区：
文献类型：
--
作者：
Nakatsura, T;Komori, H;Nishimura, Y
目的与实验设计：基于对23,040个基因的基因芯片分析，我们最近发现GPC3在人肝细胞癌中高表达，并报道了GPC3是一种新的人肝细胞癌和黑色素瘤的肿瘤标志物。GPC3在几乎所有的肝细胞癌和黑色素瘤中都有表达，但在除胎盘和胎肝以外的正常组织中不表达，是一种理想的免疫治疗肿瘤抗原。在本研究中，我们试图在BALB/c小鼠中鉴定出小鼠GPC3的CTL表位，并为此建立了一项临床前研究，以探讨GPC3作为活体肿瘤免疫治疗靶点的有效性。结果：我们在BALB/c小鼠中鉴定出一种小鼠GPC3来源的K-d限制性CTL表位多肽。将此GPC3多肽特异性CTL接种到S.C.小鼠GPC3基因(C26/GPC3)转染的COLON26肿瘤细胞(C26/GPC3)在体内引起肿瘤排斥反应，并静脉注射。将这些CTL接种到亚致死剂量照射的小鼠体内，显著地抑制了已建立的S.C.肿瘤。用该肽冲击的骨髓来源的树突状细胞接种可抑制S.C.的生长。脾C26/GPC3伴CD8(+)T细胞大量侵入肿瘤。在拒绝肿瘤细胞挑战的存活小鼠中从未观察到自身免疫反应的证据。结论：我们发现新的癌胎儿蛋白GPC3在小鼠中具有高度的免疫原性，并在没有自身免疫证据的情况下诱导了有效的抗肿瘤免疫。GPC3不仅对肝细胞癌和黑色素瘤的诊断有用，而且可能用于免疫治疗或预防这些肿瘤。
Purpose and Experimental Design: We recently identified glypican-3 (GPC3) overexpressed specifically in human hepatocellular carcinoma, as based on cDNA microarray analysis of 23,040 genes, and we reported that GPC3 is a novel tumor marker for human hepatocellular carcinoma and melanoma. GPC3, expressed in almost all hepatocellular carcinomas and melanomas, but not in normal tissues except for placenta or fetal liver, is a candidate of ideal tumor antigen for immunotherapy. In this study, we attempted to identify a mouse GPC3 epitope for CTLs in BALB/c mice, and for this, we set up a preclinical study to investigate the usefulness of GPC3 as a target for cancer immunotherapy in vivo.Results: We identified a mouse GPC3-derived and K-d-restricted CTL epitope peptide in BALB/c mice. Inoculation of this GPC3 peptide-specific CTL into s.c. Colon26 cancer cells transfected with mouse GPC3 gene (C26/GPC3) led to rejection of the tumor in vivo, and i.v. inoculation of these CTLs into sublethally irradiated mice markedly inhibited growth of an established s.c. tumor. Inoculation of bone marrow-derived dendritic cells pulsed with this peptide prevented the growth of s.c. and splenic C26/GPC3 accompanied with massive infiltration of CD8(+) T cells into tumors. Evidence of autoimmune reactions was never observed in surviving mice that had rejected tumor cell challenges.Conclusions: We found the novel oncofetal protein GPC3 to be highly immunogenic in mice and elicited effective antitumor immunity with no evidence of autoimmunity. GPC3 is useful not only for diagnosis of hepatocellular carcinoma and melanoma but also for possible immunotherapy or prevention of these tumors.