"UNIQUE" TUMOR ANTIGENS RECOGNIZED BY CD8+ T CELLS

长期的目标是了解基因的起源和 独特的(即各自不同的)抗原的生物学功能。 这些抗原在移植时会导致退行性肿瘤的排斥反应。 移植到幼小鼠体内和进展性肿瘤中 免疫的小鼠。CD8+T细胞识别的两种独特抗原 将被分析：那些必须被回归者丢失才能 在幼稚的小鼠和那些可以被进步者保留的小鼠中成长 变种。在第一个目标中，将确定一个表达式是否 体细胞突变的p68多肽确实引起了对 退化性肿瘤，通过分析突变基因是否通过 抗原丢失变异体从进展者恢复为退化者 表型。如果观察到这一点，将进一步确定是否重新- 即使在已确诊的癌症中，这种抗原的表达也足以 引发肿瘤排斥反应。在目标2中，将研究p68的哪些变化 在各种癌症中观察到解旋酶(特别是突变和上调- 表达的调节)，以及已经观察到的点突变 基因的智商结构域导致致癌特性，而 野生型p68基因作为肿瘤抑制基因。目标3的主要目标是 确认或驳斥唯一排斥抗原这一普遍原理 紫外线诱导的肿瘤是由于一种表达的蛋白质的体细胞突变 在癌细胞中处于高水平。CD8+T细胞定义的唯一5117-RE 不断被进展变异体丢失的肿瘤抗原将是 用作模型。如果发现了突变基因，潜在的 这些突变对恶性过程的意义将被研究。 第四个目标将是确定独特抗原的遗传起源。 保留在原发和变异的进展性肿瘤上，并且 不足以引起幼小鼠的肿瘤排斥反应。我们将对其进行检查 这些抗原是否也是由体细胞肿瘤特异性编码的 突变以及这些突变多肽是相等还是更少 免疫原性高于仅由退化性肿瘤表达的突变多肽。 最后，我们将确定突变体的杂合性丢失 在进展性肿瘤上编码独特抗原的基因负责 某些CTL表位对免疫选择的极端抗药性，我们 将在标准分析中分析突变基因与 恶性的发展。

The long-term objective is to understand the genetic origins and biological functions of unique, (i.e. individually distinct) antigens. These antigens lead to rejection of regressor tumors when transplanted into naive mice and of progressor tumors when transplanted into pre- immunized mice. Two types of unique antigens recognized by CD8+ T cells will be analyzed: those that must be lost by regressors before they can grow in a naive mice and those that can be retained by progressor variants. In the first Aim, it will be determined whether expression of a somatically mutated p68 peptide indeed gives rise to the rejection of the regressor tumor, by analyzing whether re-expression of the mutant gene by an antigen-loss variant reverts from a progressor to a regressor phenotype. If this is observed, it will further be determined whether re- expression of this antigen is sufficient even in established cancer to elicit tumor rejection. In Aim 2, it will be studies which changes in p68 helicase are observed in various cancers (in particular mutations and up- regulation of expression), and whether the already observed point mutation in the IQ domain of the gene results in oncogenic properties, while the wild-type p68 acts as a tumor suppressor gene. The main goal of Aim 3 is to confirm or refute the general principal that unique rejection antigens of UV-induced tumors are due to somatic mutations in a protein expressed at high levels in the cancer cells. The CD8+ T cell-defined unique 5117-RE tumor antigen which is consistently lost by progressor variants will be used as the model. If a mutant gene is identified, the potential significance of the mutations for the malignant process will be studied. The fourth Aim will be to identify the genetic origins of unique antigens that are retained on primary and variant progressor tumors and are insufficient to elicit tumor rejection by naive mice. It will be examined whether these antigens are also encoded by somatic tumor-specific mutations and whether these mutant peptides are equally or less immunogenic than mutant peptides expressed only by regressor tumors. Finally, we will determine whether loss of heterozygosity of the mutant genes encoding unique antigens on the progressor tumors is responsible for the extreme resistance of certain CTL epitopes to immunoselection, and we will analyze in standard assays the relevance of the mutant genes to the development of malignancy.