MUC-1 related cancer immunity: determinants and predictive significance

描述（由申请人提供）：人粘蛋白（MUC）家族成员MUC1是一种跨膜糖蛋白，主要由正常上皮细胞以低水平表达，癌细胞以高水平表达。大多数上皮腺癌，包括乳腺癌和卵巢癌，过度表达MUC1，更重要的是，可能会促进抗MUC1抗体，这与更有利的预后相关。通过扩展，我们假设癌症的风险可能会降低预先存在的MUC1特异性免疫和组装有说服力的横截面和病例对照数据，这表明各种医疗和生殖事件，包括乳腺炎，宫内节育器的使用，输卵管结扎，骨折可以预测抗MUC1抗体的存在和降低卵巢癌的风险。为了验证这些“回顾性”观察，我们现在提出一项前瞻性研究，有三个目标。在目标1下，我们将在可能影响MUC1免疫的事件之前或最早阶段识别女性，并记录与MUC1相关的体液和细胞免疫应答的变化。在目标二下，我们将在任何治疗之前从卵巢癌患者中收集（术前）血液样本，以确定肿瘤产生的免疫（体液和细胞）与目标一中研究的医疗和生殖事件可能产生的免疫之间的相似性或差异。这些分析的目的是鉴定在这种情况下具有免疫原性的MUC1表位和产生的免疫应答类型，以便我们可以改进用于测量目的3中的抗MUC1抗体的测定。在这一目标下，我们将在护士健康研究（NHS）中进行巢式病例对照研究，以直接评估抗MUC1抗体在卵巢癌发生前多年的预测价值。我们将选择NHS队列成员，其血浆标本在他们患卵巢癌前至少4年可用，并匹配对照，并使用前瞻性流行病学数据测量抗MUC1抗体以确定抗体的实际预测值，而不是推断值。我们的研究结果可以为开发一种安全的卵巢癌和其他MUC1表达肿瘤的癌症预防疫苗提供基础。

DESCRIPTION (provided by applicant): Human mucin (MUC) family member, MUC1, is a transmembrane glycoprotein expressed in low levels by normal, primarily, epithelial cells and high levels by cancer cells. Most epithelial adenocarcinomas, including those from the breast and ovary, over-express MUC1 and, more importantly, may promote anti-MUC1 antibodies, which correlate with more favorable prognosis. By extension, we hypothesized that the risk for cancer might be reduced by pre-existing MUC1-specific immunity and assembled persuasive cross-sectional and case-control data, which suggest that various medical and reproductive events, including breast mastitis, IUD use, tubal ligation, and bone fracture may predict the presence of anti-MUC1 antibodies and lower ovarian cancer risk. To validate these "retrospective" observations, we now propose a prospective study with three aims. Under aim 1, we will identify women either before or at the earliest stages of events that may affect MUC1 immunity and document changes in humoral and cellular immune responses related to MUC1. Under aim two, we will collect (pre-operative) blood specimens from women with ovarian cancer prior to any therapy to identify similarities or differences between tumor-generated immunity (both humoral and cellular) and the immunity that may be generated by the medical and reproductive events studied in aim 1. A goal of these analyses will be to identify the epitopes of MUC1 that are immunogenic in this setting and the types of immune responses generated in order that we may refine the assays used for measuring anti- MUC1 antibodies in aim 3. Under this aim, we will perform a nested case-control study within the Nurses Health Study (NHS) to assess directly the predictive value of anti-MUC1 antibodies many years prior to the development of ovarian cancer. We will select NHS cohort members with a plasma specimen available at least 4 years before they developed ovarian cancer and matched controls and measure anti-MUC1 antibodies to determine actual, rather than inferred, predictive value of antibodies using prospective epidemiologic data. The findings of our study could provide the basis for developing a safe cancer- preventing vaccine for ovarian cancer and perhaps other MUC1-expressing tumors.