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.
The proposed research will comprehensively study the association between MDSCs and ovarian cancer prognosis. If strong associations are identified, such information can be used in the clinical setting in identifying most promising candidates for novel immunotherapeutic approaches.
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