Mechanisms of Immune Suppression in Ovarian Cancer

instaictions): Ovarian cancer has a high mortality rate and despite some improvements in survival with new chemotherapies, the cure rate has not improved in decades. While clinical features (e.g. stage) are excellent indicators of outcome, there remains significant variability in outcomes. Although recognized as an immune reactive malignancy, ovarian cancer eludes immunity due to a tumor-induced, complex immune suppressive network. In this project, we will examine determinants of immune suppression at an inherited level and at the level of the tumor microenvironment. We will then integrate inherited variation and novel tumor phenotypes with rich clinical annotation in biological models of these microenvironmental relationships and their impact on survival. We will study three unique elements of this network, specifically CD4+ T regulatory cells (Tregs), CD8+ Tregs, and PD-1 + expression on intratumoral dendritic cells (DC). Our general hypothesis is that immune suppression, which reflects a sophisticated interaction of a network of genes, molecules, and cells, contributes to ovarian cancer pathogenesis. This hypothesis is examined in the following aims. Specific Aim 1: To evaluate the association between inherited variation in 32 immune regulatory genes and overall survival among invasive ovarian cancer cases. Specific Aim 2: To determine the role of CD8+ Tregs and PD-1+ DC in the ovarian cancer immune microenvironment. Specific Aim 3: To assess the role of inherited variation in immune regulatory genes and intermediate tumor phenotypes in a multivariate model of survival in'ovarian cancer. Our proposed transdisciplinary project integrates population and basic research to increase our understanding of the immunologic mechanisms guiding relationships between host factors, immunologic tumor characteristics, and ovarian cancer outcome. Outcomes of this work will direct subsequent immune therapies in our already existing immunotherapy program. The clinically useful information developed in this grant will include the (1) identification of targets to block the suppressive mechanisms that ovarian cancers employ to evade immune surveillance and eradication, (2) identification of ways to better personalize use of novel immune-based therapies for the prevention of ovarian cancer recun'ence, and (3) identification of novel immune targets not currently addressed with immune-based therapies. Core Utilization Administrative, Biospecimens and Patient Registry, Biostatistics, and Animal Models Cores. Extramural Interactions Ovarian Cancer Association Consortium (OCAC), Dr. Mary L. Disis (University of Washington). Letters of Support Dr. Andrew Berchuck (Duke University), Dr. Georgia RELEVANCE (See Instructions): The proposed work will improve our understanding of the immune system and ovarian cancer pathogenesis. The results of this study will potentially be useful for ovarian cancer prognosis and the development of new therapeutic strategies.