Ring finger protein 43 as a new target for cancer immunotherapy
Ring finger protein 43 as a new target for cancer immunotherapy
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DOI：
10.1158/1078-0432.ccr-04-0104
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发表时间：
2004-12-15
影响因子：
11.5
通讯作者：
Tahara, H
中科院分区：
文献类型：
--
作者：
Uchida, N;Tsunoda, T;Tahara, H
我们利用基因芯片进行了全基因组的探索，并成功地鉴定了一种新的肿瘤相关抗原(TAA)，它可以诱导强大的针对肿瘤细胞的细胞毒性T淋巴细胞(CTL)。在我们之前的研究中，我们通过使用包含23,040个基因的全基因组cDNA微阵列的基因表达谱识别了多个新基因。其中，我们选择RNF43(RING Finger Protein 43)作为结肠癌细胞表达的TAA的候选基因。在这项研究中，我们检测了RNF43蛋白是否含有限制于人类白细胞抗原A*0201或人类白细胞抗原-A*2402的抗原表位。用与HLA-A*0201(ALWPWLLMA和ALWPWLLMAT)和HLA-A*2402(NSQPVWLCL)结合的多肽在刺激下成功地诱导出CTL克隆，这些CTL克隆不仅对多肽冲击靶标具有特异性杀伤活性，而且对表达RNF43和相应HLAs的肿瘤细胞也具有特异性杀伤活性。两个人类白细胞抗原A2限制性表位介导的杀伤活性较弱，而人类白细胞抗原A24表位介导的肿瘤杀伤作用明显较好。这些发现可能是由于肿瘤对RNF43-11(IX)和RNF43-11(X)的自然呈现不佳或T细胞受体对这些特定表位的亲和力较差所致。这些结果有力地表明RNF43是一种新的结肠癌TAA。此外，这些结果还表明，我们的策略可能是一种有前景的策略，可以有效地发现临床上有用的TAA。
We have performed genome-wide exploration by using cDNA microarray profiling, and successfully identified a new tumor-associated antigen (TAA) that can induce potent cytotoxic T lymphocytes (CTLs) specific to tumor cells. In our preceding study, we identified multiple new genes by using gene expression profiling with a genome-wide cDNA microarray containing 23,040 genes. Among them, we selected RNF43 (ring finger protein 43) as a promising candidate for a TAA expressed by colon cancer cells. In this study, we examined whether the RNF43 protein contains antigenic epitope peptides restricted to HLA-A*0201 or HLA-A*2402. The CTL clones were successfully induced with stimulation by using the peptides binding to HLA-A*0201 (ALWPWLLMA and ALWPWLLMAT) and HLA-A*2402 (NSQPVWLCL), and these CTL clones showed the cytotoxic activity specific to not only the peptide-pulsed targets but also the tumor cells expressing RNF43 and respective HLAs. Lytic activities mediated by two HLA-A2-restricted epitopes were marginal, whereas tumor lysis mediated by the HLA-A24 epitope was clearly better. These findings might be caused by the poor natural presentation of RNF43-11(IX) and RNF43-11(X) by tumors or poor T-cell receptor avidity for these specific epitopes. These results strongly suggest that RNF43 is a new TAA of colon cancer. Furthermore, these results also suggest that our strategy might be a promising one to efficiently discover clinically useful TAAs.