Identification of a Novel Tumor-Associated Antigen, Cadherin 3/P-Cadherin, as a Possible Target for Immunotherapy of Pancreatic, Gastric, and Colorectal Cancers
Identification of a Novel Tumor-Associated Antigen, Cadherin 3/P-Cadherin, as a Possible Target for Immunotherapy of Pancreatic, Gastric, and Colorectal Cancers
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DOI：
10.1158/1078-0432.ccr-08-1086
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发表时间：
2008-10-15
影响因子：
11.5
通讯作者：
Nishimura, Yasuharu
中科院分区：
文献类型：
--
作者：
Imai, Katsunori;Hirata, Shinya;Nishimura, Yasuharu
目的：为了建立癌症免疫疗法，重要的是鉴定在肿瘤细胞中强烈表达但在正常细胞中不表达的肿瘤相关抗原（TAA）。在本研究中，为了建立有效的抗癌免疫疗法，我们试图鉴定对胰腺癌有用的TAA。 实验设计：基于之前对胰腺癌的全基因组c DNA微阵列分析，我们重点关注钙粘蛋白3（CDH3）/P-钙粘蛋白作为抗癌免疫治疗的新型候选TAA。为了鉴定 HLA-A2 (A*0201) - CDH3 的限制性 CTIL 表位，我们使用了 HLA-A2.1 (HHD) 转基因小鼠 (Tgm)。此外，我们在体外和体内检测了 HLA-A2 阳性健康供体和癌症患者诱导的 CDH3 特异性 CTL 对肿瘤细胞的细胞毒性。结果：CDH3 在大多数胰腺癌和各种其他恶性肿瘤（包括胃癌和结直肠癌）中过度表达，但在非癌性对应物或许多正常成人组织中不过度表达。在使用HLA-A2.1 Tgm的实验中，我们发现CDH3-4（655-663）（FILPVLGAV）和CDH3-7（757-765）（FIIENLKAA）肽可以在Tgm中诱导HLA-A2限制性CTL。此外，在HLA-A2阳性健康供体和癌症患者中，通过体外刺激这两种肽，成功地从外周血单核细胞中诱导出肽反应性CTL，并且这些CTL对表达CDH3和HLA-A2的癌细胞表现出特异性的细胞毒性。此外，CDH3特异性CTL的过继转移可以抑制移植到非肥胖糖尿病/严重联合免疫缺陷小鼠体内的人类癌细胞的肿瘤生长。结论：这些结果表明CDH3是一种新型TAA，可用于针对包括胰腺癌在内的多种癌症的免疫治疗。
Purpose: To establish cancer immunotherapy, it is important to identify the tumor-associated antigens (TAA) that are strongly expressed in the tumor cells but not in the normal cells. In this study, to establish an effective anticancer immunotherapy, we tried to identify the useful TAA of pancreatic cancer.Experimental Design: Based on a previous genome-wide c DNA microarray analysis of pancreatic cancer, we focused on cadherin 3 (CDH3)/P-cadherin as a novel candidate TAA for anticancer immunotherapy. To identify the HLA-A2 (A*0201) - restricted CTIL epitopes of CDH3, we used HLA-A2.1 (HHD) transgenic mice (Tgm). Furthermore, we examined the cytotoxicity against the tumor cells in vitro and in vivo of CTLs specific to CDH3 induced from HLA-A2-positive healthy donors and cancer patients.Results: CDH3 was overexpressed in the majority of pancreatic cancer and various other malignancies, including gastric and colorectal cancers, but not in their noncancerous counterparts or in many normal adult tissues. In the experiment using HLA-A2.1 Tgm, we found that the CDH3-4(655-663) (FILPVLGAV) and CDH3-7(757-765) (FIIENLKAA) peptides could induce HLA-A2-restricted CTLs in Tgm. In addition, peptides-reactive CTLs were successfully induced from peripheral blood mononuclear cells by in vitro stimulation with these two peptides in HLA-A2-positive healthy donors and cancer patients, and these CTLs exhibited cytotoxicity specific to cancer cells expressing both CDH3 and HLA-A2. Furthermore, the adoptive transfer of the CDH3-specific CTLs could inhibit the tumor growth of human cancer cells engrafted into nonobese diabetic/severe combined immunodeficiency mice.Conclusions: These results suggest that CDH3 is a novel TAA useful for immunotherapy against a broad spectrum of cancers, including pancreatic cancer.