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Understanding suppression of T effector memory cells by mediators of the ovarian carcinoma microenvironment

DFG HU 1824/9-1

Ovarian cancer is the most lethal gynecological malignancy with approximately 60.000 new cases annually in the United States and the European Union. It is usually diagnosed at advanced stages and even after successful first-line therapy most patients develop relapse of disease. The high grade serous carcinoma (HGSOC) subtype is the most common and aggressive among six different ovarian cancer entities. Advanced stages are usually characterized by an excess accumulation of peritoneal effusion, termed ascites, which contains cytokines, growth factors, lipids and other soluble mediators secreted by tumor and tumor-associated host cells. Besides tumor cells, ovarian cancer ascites contains different immune cells, among them macrophages, CD4+ and CD8+ T cells. The peritoneal fluid contributes directly to the dissemination of tumor cells to the omentum and peritoneum, a process referred to as transcoelomic metastasis, as well as to suppression of an anti-tumor response.

Several observations indicate that the immune system plays a crucial role in ovarian cancer. Thus, an increased accumulation of intratumoral T cells delays recurrence of the disease, the checkpoint blockade by anti-PD1 antibody showed efficacy in a subset of patients and the number of somatic mutations and mutation-related neoepitopes detectable by immune cells correlate with overall survival. These findings point out to the importance of identifying the factors restricting the anti-tumor immune response and understanding the mechanisms.

In order to characterize factors in the HGSOC environment that suppress signaling proteins in CD8+ TEM cells and thereby their activation, to elucidate the underlying mechanisms and to identify potentially relevant biomarkers we propose to address the following objectives (Figure 1).

Figure 1. Proposed work-flow for identification of factors and mechanisms of TAT suppression by ovarian cancer ascites.