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，在正常上皮细胞中低水平表达，在癌细胞中高水平表达。大多数上皮腺癌，包括乳腺和卵巢上皮腺癌，都过表达MUC1，更重要的是，可能促进抗MUC1抗体的产生，这与较好的预后相关。进一步，我们假设存在muc1特异性免疫可能会降低患癌风险，并收集了有说服力的横断面和病例对照数据，这些数据表明，各种医疗和生殖事件，包括乳房炎、宫内节育器使用、输卵管结扎和骨折可能预测抗muc1抗体的存在和降低卵巢癌风险。为了验证这些“回顾性”观察结果，我们现在提出了一个有三个目标的前瞻性研究。在目标1下，我们将在可能影响MUC1免疫的事件之前或早期阶段确定女性，并记录与MUC1相关的体液和细胞免疫反应的变化。在目标2下，我们将在任何治疗之前收集卵巢癌妇女的（术前）血液标本，以确定肿瘤产生的免疫（体液和细胞）与目标1中研究的医疗和生殖事件可能产生的免疫之间的异同。这些分析的目标将是确定MUC1在这种情况下具有免疫原性的表位和产生的免疫反应类型，以便我们可以改进用于测量目标3中抗MUC1抗体的测定方法。在这一目标下，我们将在护士健康研究（NHS）中进行一项巢式病例对照研究，直接评估抗muc1抗体在卵巢癌发展多年前的预测价值。我们将选择在患卵巢癌前至少4年有血浆标本的NHS队列成员和匹配的对照，并测量抗muc1抗体，以确定实际的，而不是推断的，使用前瞻性流行病学数据的抗体的预测价值。我们的研究结果可以为开发卵巢癌和其他muc1表达肿瘤的安全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.