Identification of Genes Encoding Lung Cancer Antigens Recognized by Cytotoxic T-lymphocytes and Development of Cancer Vaccines

肺癌是世界上最常见的恶性肿瘤之一，也是少数几种发病率持续上升的恶性肿瘤之一。进展不佳的非小细胞肺癌患者的预后非常差，因为化疗是这些患者唯一的治疗方式，而且非小细胞肺癌患者对抗癌药物的应答率很低。因此，开发新的肺癌治疗方法是必要的。特异性免疫治疗是肺癌治疗中最突出和最有希望的手段之一。我们研究了人类白细胞抗原-A2402限制性细胞毒性T淋巴细胞(CTL)识别的肿瘤排斥抗原，发现多药耐药相关蛋白3(MRP3)是一种由HLA.-A2402限制性细胞毒性T淋巴细胞(CTL)识别的肿瘤排斥抗原。MRP3用…表示不同组织类型和来源的肿瘤细胞数量差异较大。目前已鉴定出四种主要的MRP3来源的抗原肽，它们都被CTL识别，每一种都具有体外免疫原性。我们还报道了三个新发现的肿瘤抗原基因，包括一个未报道的基因，暂时称为克隆83，以及两个已知基因，BTB结构域包含-2(BTBD2)和发夹结合蛋白。这些基因在大多数肺癌细胞系、卵巢癌和肾癌细胞系的mRNA水平上均有优先表达。在肺癌和其他肿瘤组织标本中证实了这些基因的表达。克隆83、BTBD2和发夹结合蛋白分别编码2、1和1个能被人类白细胞抗原A2402限制性CTL识别的表位多肽，每个多肽都具有体外免疫原性。这些结果表明，这些基因和多肽是潜在的候选肿瘤疫苗的人类白细胞抗原-A24^+肺癌患者。较少

Lung cancer is among the most commonly occurring malignancies in the world and is one of the few that continuous to show an increasing incidence. Prognosis of patients with unrespectable progressive stages of non-small cell lung cancer is very poor, since chemotherapy is the only modality for these patients and response rate to anti-cancer drugs in patients with non-small cell lung cancer is low. Therefore, development of new therapeutic modalities for lung cancer is necessary. Specific immunotherapy is one of the most prominent and hopeful modalities in lung cancer treatment. We have investigated tumor rejection antigens recognized by HLA-A2402-restricted cytotoxic T lymphocytes (CTLs) established from T cells infiltrating into lung cancer, and we show that a multidrug resistance-associated protein 3 (MRP3) is a tumor rejection antigen recognized by HLA.-A2402-restricted cytotoxic T-lymphocytes (CTLs) established from T cells infiltrating into lung adenocarcinoma. MRP3 is expressed in … More differing quantities in tumor cells of various tissue types and origins. Four dominant MRP3-derived antigenic peptides which are recognized by the CTLs have been identified, each possessing in vitro immunogenicity. We also reported three newly identified tumor antigen genes, including one unreported gene, temporarily referred to as clone 83, and two known genes, BTB domain containing-2 (BTBD2) and hairpin-binding protein. These genes were preferentially expressed in most of the cell lines of lung cancer, and also of ovarian cancer and renal cell carcinoma at the mRNA level. The expression of these genes was confirmed in lung and other cancer tissue specimens. Clone 83, BTBD2, and hairpin-binding protein encoded 2, 1, and 1 epitope peptides that can be recognized by HLA-A2402-restricted CTLs, respectively, and each peptides possessing in vitro immimogenicity. These results suggest that these genes and peptides are potential candidates for cancer vaccines in HLA-A24^+ patients with lung cancer. Less