DENDRITIC CELLS--A NEW TUMOR ANTIGEN DISCOVERY SYSTEM

这项提案的目标是建立一个肿瘤抗原发现 使用人树突状细胞作为抗原呈递细胞的系统， 人T细胞体外培养的最新技术进展， 以尝试鉴定候选肿瘤特异性抗原。这是一部小说 在这一领域的所有以前的工作中， 来自癌症患者的T细胞和肿瘤细胞的次级应答， 抗原呈递细胞几位调查人员最近的证据表明， 癌症患者T细胞功能的严重缺陷， 对于确定潜在的肿瘤靶点来说，来源不是最佳的。我们 假设使用来自健康供体的幼稚T细胞和一种新的， 依赖于树突状细胞的强大的体外引发系统，应该 绕过体内肿瘤诱导的免疫抑制问题， 召回中未检测到的所有潜在肿瘤抗原 应答 我们将重点关注尚未发现特异性抗原的肺癌。 HLA-A2限制性元件，最常见的人类类 I等位基因。重点将放在肽的能力，自然， 由肿瘤处理，以在体外引发CD 8 + T细胞应答，当 由树突状细胞呈递。此外，整个肿瘤蛋白将被 分离，然后由树突细胞处理和呈递， 探索其引发肿瘤特异性辅助性CD 4 + T细胞的潜力 体外反应。一种肿瘤抗原MUC-1粘蛋白 在乳腺癌和胰腺癌上鉴定的是LAOS， 肺腺癌因此，除了确定新的肺部肿瘤， 抗原，我们将测试肺肿瘤粘蛋白刺激的全部潜力， 当由树突状细胞呈递时，CD 8+和CD 4 + T细胞。具体目标 为： 1.以树突状细胞作为I类抗原的敏感指标 限制性肿瘤特异性，可以在体外引发CD 8 + T反应。 2.使树突细胞能够摄取并处理肿瘤细胞 蛋白质，并表明那些可以在体外引发CD 4 + T细胞应答。 在展示了这种方法的实用性之后，这些方法的最终目标是 研究将使用已鉴定的肽和蛋白质来设计 肺癌疫苗或促进过继性T细胞治疗 癌

The goals of this proposal are to create a tumor antigen discovery system using human dendritic cells as antigen presenting cells and the most recent technological advances in in vitro culture of human T cells, to attempt to identify candidate tumor specific antigens. This is a novel approach in as much as all previous work in this area has been utilized secondary responses of T cells from cancer patients and tumor cells as antigen presenting cells. Recent evidence from several investigators point towards profound defects in cancer patients' T cell function, making this source less than optimal for defining potential tumor targets. We hypothesize that using naive T cells from healthy donors and a new, powerful in vitro priming system dependent on dendritic cells, should bypass the problem of tumor induced immune suppression in vivo and uncover all potential tumor antigens which have remained undetected in the recall responses. We will focus on lung cancer for which no specific antigens have been identified and on HLA-A2 restricting element, the most common human Class I allele. Emphasis will be placed on the ability of peptides, naturally processed by the tumor, to prime CD8+ T cell responses in vitro, when presented by dendritic cells. In addition, whole tumor proteins will be fractionated and then processed and presented by the dendritic cells to explore their potential of priming tumor-specific helped CD4+ T cell responses in vitro. One tumor antigen, MUC-1 mucin, that we have identified on breast and pancreatic adenocarcinomas is laos expressed by lung adenocarcinomas. Thus in addition to identifying new lung tumor antigens, we will test the full potential of lung tumor mucin to stimulate CD8+ and CD4+ T cells when presented by dendritic cells. Specific aims are: 1. To use dendritic cells as sensitive indicators of Class I restricted tumor specific that can prime CD8+ T responses in vitro. 2. To allow dendritic cells to take up and process tumor cell proteins and indicate those that can prime CD4+ T cell responses in vitro. Having shown the utility of this method, the ultimate goal of these studies will be to use the identified peptides and proteins for designing lung cancer vaccines or facilitating adoptive T cell therapy of lung cancer.