Myeloid Derived Suppressor Cells in Ovarian Carcinogenesis

我们提出了一个全面的遗传和分子流行病学调查髓源性抑制细胞（MDSC）在卵巢癌预后中的作用。这些细胞已被证明与缺陷的树突状细胞功能和通过多种机制抑制CD4+和CD8+ T细胞应答相关。这是一个非常重要的项目，用于预后的风险分类，并确定可能干扰卵巢癌患者免疫治疗方法疗效的因素。为了实现这一目标，我们提出了三个创新的目标，允许在一个精心设计的流行病学框架中首次全面调查MDSC在卵巢癌发生中的作用。在具体目标1中，我们将受益于我们与卵巢癌协会联盟的强大合作关系，这将使我们能够访问超过13，000名卵巢癌患者的非常大的队列，我们将测量假设与MDSC活性和卵巢癌结局（生存和复发）相关的基因中的单核苷酸多态性（SNP）之间的关系。这是第一项考虑基因中SNP之间的关联的研究，这些基因被认为与调节MDSC水平和癌症预后有关，特别是卵巢癌预后。在具体目标2中，我们将评估320例浆液性卵巢癌患者治疗前后肿瘤和血液样本中MDSC频率的临床特征和短期结局之间的相关性。最后，在目标3中，我们测试了显著的SNP（目标1）与来自卵巢癌患者的血液和肿瘤组织中的MDSC水平的关联，以帮助确定MDSC水平是否可能驱动SNP与目标1中所见的临床结果的显著关联。重要的是，根据这些信息，我们将使用预测模型建立一个临床工具，以识别易受不良结局影响的患者。这三个目标共同允许全面调查表型表达和遗传变异在一个重要的免疫途径中的作用，该免疫途径与卵巢癌诊断和结局时对不良临床特征的易感性相关。

We propose a comprehensive genetic and molecular epidemiological investigation of the role of Myeloid Derived Suppressor Cells (MDSCs) in ovarian cancer prognosis. These cells have been shown to be associated with defective dendritic cell function and suppression of CD4+ and CD8+ T cell response via multiple mechanisms. This is a highly significant project for risk classification for prognosis, and identification of factors that may interfere with the efficacy of immunotherapeutic treatment approaches in ovarian cancer patients. To achieve this objective we propose three innovative aims that allow the first comprehensive investigation of MDSC in ovarian carcinogenesis in a well-designed epidemiologic framework. In Specific Aim 1, we will benefit from our strong collaborative ties with the Ovarian Cancer Association Consortium, which will allow us access to a very large cohort of over 13,000 of ovarian cancer patients in which we will measure the relationship between single nucleotide polymorphisms (SNPs) in genes hypothesized to be associated with MDSC activity and ovarian cancer outcomes (survival and recurrence). This is the first study to consider the association between SNPs in genes believed relevant to modulating MDSC levels and cancer prognosis in general and ovarian cancer prognosis in particular. In Specific Aim 2, we will assess the association between clinical characteristics and short-term outcomes with MDSC frequencies in tumor and blood samples prior to and post treatment in 320 serous ovarian cancer patients. Lastly in Aim 3 we test for association of significant SNPs (Aim 1) with MDSC levels in blood and tumor tissue from patients with ovarian cancer to help determine if MDSC levels are possibly driving the significant associations of SNPs with clinical outcomes seen in Aim 1. Importantly, from this information we will build a clinical instrument using predictive models in order to identify patients susceptible to poor outcomes. Together these three aims allow for a comprehensive investigation of the roles of phenotypic expression and genetic variation in an important immune pathway relevant to susceptibility to poor clinical characteristics at diagnosis and outcomes in ovarian cancer.