HLA class l complex expression in breast cancer immunity

乳腺癌免疫中 HLA I 类复合物的表达

• 批准号: 7414086
• 负责人: Keith L. Knutson
• 金额: $ 22.18万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-23 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414086
• 关键词: Affinity; Antibodies; Antigen Presentation; Antigen Presentation Pathway; Antigens; Attention; Avidity; Biological Markers; Breast; Breast Cancer Cell; Breast Carcinoma; Cell surface; Cells; Class; Clinical Course of Disease; Complex; Cytolysis; Cytotoxic T-Lymphocytes; Defect; Disease; Disease Outcome; Down-Regulation; ERBB2 gene; Evaluation; Generations; HLA A*0201 antigen; HLA-A Antigens; HLA-A gene; HLA-A2 Antigen; Histocompatibility Antigens Class I; Immune; Immune response; Immunity; Individual; Lead; Lesion; Malignant Epithelial Cell; Methods; Modeling; Monoclonal Antibodies; Patients; Peptides; Protein Overexpression; Proteins; Research Personnel; Role playing therapy; Specific qualifier value; Surface; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Tumor Antigens; Up-Regulation; Upper arm; Vaccines; Xenograft Model; antigen processing; base; cancer cell; cell killing; cell mediated immune response; cytokine; cytotoxicity; design; improved; in vivo; malignant breast neoplasm; molecular modeling; neoplastic cell; novel therapeutics; outcome forecast; peptide I; prevent; programs; prophylactic; response; therapeutic target; tumor

DESCRIPTION (provided by applicant): Although patients with breast carcinoma mount a T cell-mediated immune response to their disease it usually progresses. Among the many escape mechanisms identified, defects in HLA class I/tumor antigen(TA) peptide complex expression by tumor cells have attracted much attention since these complexes are involved in the generation of HLA class I restricted cytolytic T cell (CTL) immunity. Previous studies have shown that HLA class I antigens are frequently down-regulated in breast cancer cells. However, it remains unknown as to how this down-modulation occurs and whether HLA-class I down-modulation correlates with the level of HLA class I/TA peptide complex expression. The lack of this information reflects the limited availability of probes to evaluate expression of HLA class I/TA peptide complexes on tumor cells, including breast carcinoma cells. In recent years, we have acquired new antibody probes that could potentially answer many questions related to loss of HLA-class I expression on breast cancer cells. These probes include single chain Fv fragments that are able to recognize HLA-class I/TA peptide complexes as well as numerous monoclonal antibodies that recognize multiple components of the antigen processing and presentation machinery. We will use these probes to define the defects that lead to the loss of HLA-class I/TA peptide complex expression, how these defects that lead to tumor immune evasion, and the relationship of this evasion to the clinical course of the disease. The model antigen we will use to examine HLA-class I expression is HER-2/neu, an antigenic protein overexpressed on nearly 20-30% of breast cancers. We will then examine in xenograft models whether upregulation of the complexes in vivo can improve sensitivity to T cell killing. The specific aims are: To examine whether the affinity, avidity, and stability of scFVs, that recognize HLA-A*0201:HER2/neupeptide complexes on breast cancer cells, can be improved with molecular modeling techniques (2) To examine whether defects in the APM downregulate HLA-A*0201-HER2/neu peptide complexes on breast carcinoma cells, (3) To examine whether HLA-A* 0201-HER2/neu peptide complex downregulation reduces breast cancer cell recognition and cytotoxicity by HLAA* 0201-HER2/neu peptide-specific CTL, (4) To examine whether HLA-A*0201-HER2/neu peptide complex downregulation in breast cancer lesions has a negative impact on the clinical course of the disease, and (5) To examine whether exogenous agents can restore normal expression of APM components and HLA-A*0201-HER2/neu peptide complexes in vivo. We expect that the results from this study will lead to an improved understanding of the impact of HLA-class I loss on tumor immune evasion. The results will likely lead to the identification of specific molecule associated with antigen presentation that could be either a novel therapeutic target or biomarker of disease outcome.

描述（由申请人提供）：尽管乳腺癌患者对其疾病产生T细胞介导的免疫应答，但其通常进展。在许多逃逸机制中，肿瘤细胞表达的HLA I类/肿瘤抗原（TA）肽复合物的缺陷引起了人们的广泛关注，因为这些复合物参与了HLA I类限制性溶细胞性T细胞（CTL）免疫的产生。以前的研究表明，HLA I类抗原在乳腺癌细胞中经常下调。然而，这种下调是如何发生的以及HLA I类下调是否与HLA I类/TA肽复合物表达水平相关仍然是未知的。该信息的缺乏反映了用于评估肿瘤细胞（包括乳腺癌细胞）上HLA I类/TA肽复合物表达的探针的有限可用性。近年来，我们已经获得了新的抗体探针，可以潜在地回答与乳腺癌细胞上HLA I类表达丧失相关的许多问题。这些探针包括能够识别HLA-I类/TA肽复合物的单链Fv片段以及识别抗原加工和呈递机制的多种组分的许多单克隆抗体。我们将使用这些探针来定义导致HLA I类/TA肽复合物表达丧失的缺陷，这些缺陷如何导致肿瘤免疫逃避，以及这种逃避与疾病临床过程的关系。我们将用于检测HLA I类表达的模型抗原是HER-2/neu，这是一种在近20-30%的乳腺癌中过表达的抗原蛋白。然后，我们将在异种移植模型中检查体内复合物的上调是否可以提高对T细胞杀伤的敏感性。具体目标是：为了检查识别HLA-A*0201：乳腺癌细胞上的HER 2/neu肽复合物可以通过分子建模技术得到改善（2）检查APM中的缺陷是否下调乳腺癌细胞上的HLA-A*0201-HER 2/neu肽复合物，（3）检查HLA-A* 0201-HER 2/neu肽复合物下调是否会降低HLAA* 0201-HER 2/neu肽特异性CTL对乳腺癌细胞的识别和细胞毒性，（4）检查乳腺癌病变中HLA-A*0201-HER 2/neu肽复合物下调是否对疾病的临床进程产生负面影响，（5）检测外源性药物是否能在体内恢复APM组分和HLA-A*0201-HER 2/neu肽复合物的正常表达。我们希望这项研究的结果将有助于更好地理解HLA I类缺失对肿瘤免疫逃避的影响。这些结果将可能导致识别与抗原呈递相关的特异性分子，其可能是新的治疗靶点或疾病结果的生物标志物。