Aberrant expression and potency as a cancer immunotherapy target of inhibitor of apoptosis protein family, Livin/ML-IAP in lung cancer.
Aberrant expression and potency as a cancer immunotherapy target of inhibitor of apoptosis protein family, Livin/ML-IAP in lung cancer.
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发表时间：
2005-02
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通讯作者：
Hiroyuki Hariu;Y. Hirohashi;T. Torigoe;H. Asanuma;M. Hariu;Y. Tamura;K. Aketa;Chika Nabeta;
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作者：
Hiroyuki Hariu;Y. Hirohashi;T. Torigoe;H. Asanuma;M. Hariu;Y. Tamura;K. Aketa;Chika Nabeta;
CD8(+)CTL在肿瘤免疫应答中具有重要作用。虽然越来越多的肿瘤相关抗原可以被CTL识别，但在肺癌中已知的肿瘤相关抗原数量有限。此外，由于它们中的一些在非癌组织中表达，它们在肿瘤免疫治疗中的应用存在局限性。Livin/ML-IAP是最近发现的凋亡抑制蛋白(IAP)家族之一，在黑色素瘤细胞中高表达。在这份报告中，我们发现Livin/ML-IAP在许多肺癌细胞系和原发肺癌组织中异常表达，而在正常组织中未检测到，包括肺组织。为了鉴定Livin/ML-IAP的人类白细胞抗原-A24限制性T细胞表位，从该蛋白的氨基酸序列中筛选出8个多肽，并对其与人类白细胞抗原-A24的结合亲和力进行筛选。结果表明，Livin7肽(氨基酸序列，KWFPSCQFLL)与人类白细胞抗原A24的亲和力最高。用Livin7多肽体外刺激HLAA24阳性肺癌患者的外周血淋巴细胞，从5例Livin/ML-IAP阳性肺癌患者中有4例成功地诱导出多肽特异性CTL，而在其癌组织中未见Livin/ML-IAP表达的患者中任何一例成功地诱导出多肽特异性CTL。此外，Livin7多肽诱导的CTL对Livin/ML-IAP(+)肺癌细胞株有一定的杀伤作用，且对HLAA24有限制作用。提示Livin/ML-IAP可能是肺癌免疫治疗的良好靶抗原，Livin7多肽可能成为治疗HLAA*2402(+)/Livin(+)肺癌患者的有效多肽疫苗。
CD8(+) CTLs have an essential role in immune response against tumor. Although an increasing number of tumor-associated antigens that can be recognized by CTLs have been identified from human tumors, a limited number of tumor-associated antigens is known in lung cancer. In addition, because some of them are expressed in noncancerous tissues, there exist limitations in their application to tumor immunotherapy. Livin/ML-IAP is one of recently identified inhibitor of apoptosis protein (IAP) family, which is overexpressed in melanoma cells. In this report, we show that Livin/ML-IAP is aberrantly expressed in many lung cancer cell lines and primary lung cancer tissues, whereas it is not detectable in normal tissues, including lung by reverse transcription-PCR methods. To identify HLA-A24-restricted T-cell epitopes of Livin/ML-IAP, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. It was revealed that Livin7 peptide (amino acid sequence, KWFPSCQFLL) had the highest affinity to HLA-A24. By stimulating peripheral blood lymphocytes of HLA-A24-positive lung cancer patients with Livin7 peptide in vitro, the peptide-specific CTLs were successfully induced from four of five patients with Livin/ML-IAP-positive lung cancer but not from any of four patients without Livin/ML-IAP expression in their cancer tissues. Furthermore, the CTLs induced by Livin7 peptide showed cytotoxicity against Livin/ML-IAP(+) lung cancer cell lines in an HLA-A24-restricted manner. Our data suggest that Livin/ML-IAP may be an excellent target antigen in immunotherapy for lung cancer and Livin7 peptide may serve as a potent peptide vaccine for HLA-A*2402(+)/Livin(+) lung cancer patients.