Role of extracellular matrix remodeling on high-grade serous ovarian carcinoma immune evasion

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The broad goal of the proposed work is to understand how the hypoxia-induced extracellular matrix (ECM) remodeling in ovarian cancer affects immune evasion. Understanding this concept would have a broad impact on identifying effective immunotherapies for ovarian cancer, a particularly deadly form of cancer in women. The ECM not only provides structural and biochemical support to tumor tissue, but also the ECM undergoes remodeling which alters the composition and mechanical properties of the tumor microenvironment, directly influencing immune evasion mechanisms. With this in mind, it has been established that hypoxia can influence tumor immunosuppression and this inadequate tissue oxygen, or hypoxia, promotes ECM remodeling. However, little is known about the role of the hypoxia-induced ECM in immune evasion and response to immunotherapy in ovarian cancer. Unfortunately, there is a scarcity of preclinical models providing recapitulation of the hypoxia-induced ECM remodeling of ovarian tumors. Thus, new technologies that allow the study of the hypoxia-induced ECM remodeling and its impact on immune evasion are crucially required. In studies leading to this application, we developed a patient-derived 3D tissue culture system capable of recapitulating the hypoxia-induced ECM and tumor-immune interactions. Specifically, we will utilize engineering approaches and patient-derived samples in order to assess the effect of the hypoxia-induced ECM remodeling on the tumor-immune cycle and further validate new treatments to overcome immune evasion. Successful completion of the proposed work will allow us to investigate the role of the hypoxia-induced ECM remodeling on cancer immune evasion, to identify how tumors escape immune surveillance, and to ascertain novel strategies to re-sensitize cancer cells to immune cells reducing tumor immune evasion in a precision-based manner.