ACTIVITY OF BREAST CANCER ASSOCIATED ANTIGEN

乳腺癌相关抗原的活性

• 批准号: 2443365
• 负责人: JOSEPH A MOLLICK
• 金额: $ 7.66万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443365
• 关键词: MHC class II antigen; adenocarcinoma; apoptosis; biological signal transduction; breast neoplasms; flow cytometry; gene induction /repression; glycoproteins; hormone regulation /control mechanism; multiple myeloma; neoplasm /cancer immunology; protein structure function; steroid hormone; tissue /cell culture; tumor antigens

DESCRIPTION (Applicant's Description): The lack of clinically significant immune responses directed against either hematologic or solid tumors is striking. Failure to generate immunity to tumors may be due to the inability of the tumors to present tumor-specific antigens or active inhibition of such responses by soluble or cell surface molecules expressed by the tumors. Muc-1 is a cell surface molecule, expressed widely on glandular epithelium and known to be shed into the lumenal space in breast milk. It is overexpressed on the surface of adenocarcinomas and can be found circulating in the blood of cancer patients. Despite a large number of descriptive studies on this molecule, its function is not known. The investigators' laboratory recently showed that cell surface and soluble forms of Muc-1 induce apoptosis in activated CD4+ T cells. Moreover, Muc-1 must be coexpressed with MHC class II molecules in order for it to induce apoptosis. These data suggest an immunomodulatory function of Muc-1 that may be used by tumors that express it to suppress immune responses to them. They propose to investigate both the physiology and the pathophysiology of Muc-1. They have designed several approaches to isolate the counter receptor on T cells that mediates the Muc-1 death signal. Experiments will be performed that elucidate the role of class II molecules in Muc-l-mediated apoptosis. Specifically, the applicants will investigate the possibility that Muc-1 binds to class II heterodimers in a non-covalent fashion reminiscent of viral superantigens, but with opposite consequences for the T cell. They also plan to focus on the physiology of this molecule. Their working hypothesis is that Muc- 1 may be responsible for maintaining or establishing immune tolerance at an epithelial surface, especially after inflammation. The structure of Muc-1 derived peptides shows a novel secondary structure that forms a repeating "knob" on the backbone of the molecule. These "knobs" also form immunodominant epitope of the molecule. They will perform structure-function studies using Muc-1 derived peptides and site directed mutagenesis of the molecule to determine the relationship of these secondary motifs to the immunomodulatory function. Their preliminary data also suggest Muc-1 is able to transduce a signal in addition to its effect on T cells and that the result of this signal is also apoptosis. Thus, the role of Muc-1 as novel regulatory for the cells that express it will be explored with immunoprecipitation following phosphate labeling. Finally, the steroid regulation of Muc-1 will be studied in both breast cancer and myeloma cells in an effort to augment elimination of Muc-1 bearing cells in upcoming Muc-1 vaccination trials.

描述（申请人描述）：缺乏临床意义 针对血液肿瘤或实体瘤的免疫应答， 引人注目。 不能产生对肿瘤的免疫力可能是由于 肿瘤不能呈递肿瘤特异性抗原或活性 通过表达的可溶性或细胞表面分子抑制这种反应 被肿瘤感染 MUC-1是一种细胞表面分子，广泛表达于 腺上皮，已知脱落到乳房内腔中 牛奶 它在腺癌的表面过表达， 在癌症患者的血液中循环。 尽管有大量 对这种分子的描述性研究，其功能尚不清楚。 的 研究人员的实验室最近表明，细胞表面和可溶性 Muc-1形式诱导活化的CD 4 + T细胞的凋亡。 此外，Muc-1 必须与MHC II类分子共表达，以诱导 凋亡 这些数据表明Muc-1的免疫调节功能， 可能被表达它的肿瘤用来抑制对它们的免疫反应。 他们建议研究脑梗塞的生理学和病理生理学 MUC-1 他们设计了几种方法来隔离计数器 T细胞上介导Muc-1死亡信号的受体。 实验将 阐明II类分子在Muc-I介导的细胞凋亡中的作用。 凋亡 具体来说，申请人将调查 Muc-1以非共价方式与II类异二聚体结合 这让人想起病毒超抗原，但对T cell. 他们还计划关注这种分子的生理学。 他们的 工作假设是，Muc- 1可能负责维持或 在上皮表面建立免疫耐受，特别是在 炎症 Muc-1衍生肽的结构显示了一种新的 二级结构，其在所述细胞的主链上形成重复的“旋钮”。 分子。 这些“旋钮”还形成分子的免疫显性表位。 他们将使用Muc-1衍生肽进行结构-功能研究 和分子的定点诱变以确定 免疫调节功能的重要性。 他们的 初步数据还表明，Muc-1能够在 除了它对T细胞的作用之外，这种信号的结果也是 凋亡 因此，Muc-1作为新的调节细胞的作用， 表达它将被探索与免疫沉淀后磷酸 标签。 最后，Muc-1的类固醇调节将在两种情况下进行研究。 乳腺癌和骨髓瘤细胞，以增强Muc-1的消除 在即将到来的Muc-1疫苗接种试验中，